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1.
Oxid Med Cell Longev ; 2022: 9469143, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35528518

RESUMO

Background: Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2), a novel immunoregulatory protein, has been reported to regulate inflammation and apoptosis. The role of TIPE2 in cardiovascular disease, especially cardiac hypertrophy, has not been elucidated. Thus, the aim of the present study was to explore the role of TIPE2 in cardiac hypertrophy. Methods: Mice were subjected to aortic banding (AB) to induce an adverse hypertrophic model. To overexpress TIPE2, mice were injected with a lentiviral vector expressing TIPE2. Echocardiographic and hemodynamic analyses were used to evaluate cardiac function. Neonatal rat cardiomyocytes (NRCMs) and mouse peritoneal macrophages (MPMs) were isolated and stimulated with angiotensin II. NRCMs and MPM were also cocultured and stimulated with angiotensin II. Cells were transfected with Lenti-TIPE2 to overexpress TIPE2. Results: TIPE2 expression levels were downregulated in hypertrophic mouse hearts and in macrophages in heart tissue. TIPE2 overexpression attenuated pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, we found that TIPE2 overexpression in neonatal cardiomyocytes did not relieve the angiotensin II-induced hypertrophic response in vitro. Furthermore, TIPE2 overexpression downregulated TLR4 and NF-κB signaling in macrophages but not in cardiomyocytes, which led to diminished inflammation in macrophages and consequently reduced the activation of hypertrophic Akt signaling in cardiomyocytes. TLR4 inhibition by TAK-242 did not enhance the antihypertrophic effect of TIPE2 overexpression. Conclusions: The present study indicated that TIPE2 represses macrophage activation by targeting TLR4, subsequently inhibiting cardiac hypertrophy.


Assuntos
Receptor 4 Toll-Like , Fator de Necrose Tumoral alfa , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Cardiomegalia/patologia , Modelos Animais de Doenças , Inflamação/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Ratos , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
2.
J Int Med Res ; 50(5): 3000605221097490, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35510669

RESUMO

OBJECTIVE: Sodium-glucose cotransporter-2 (SGLT2) inhibitors exhibit cardioprotective properties in patients with diabetes. However, SGLT2 is not expressed in the heart, and the underlying molecular mechanisms are not fully understood. We investigated whether the SGLT2 inhibitor luseogliflozin exerts beneficial effects on high glucose-exposed cardiomyocytes via the suppression of sodium-hydrogen exchanger-1 (NHE-1) activity. METHODS: Mouse cardiomyocytes were incubated under normal or high glucose conditions with vehicle, luseogliflozin, or the NHE-1 inhibitor cariporide. NHE-1 activity and gene expression were evaluated by the SNARF assay and real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis, respectively. Six-week-old male db/db mice were treated with vehicle or luseogliflozin for 6 weeks, and the hearts were collected for histological, RT-PCR, and western blot analyses. RESULTS: High glucose increased NHE-1 activity and transforming growth factor (Tgf)-ß2 mRNA levels in cardiomyocytes, both of which were inhibited by luseogliflozin or cariporide, whereas their combination showed no additive suppression of Tgf-ß2 mRNA levels. Luseogliflozin attenuated cardiac hypertrophy and fibrosis in db/db mice in association with decreased mRNA and protein levels of TGF-ß2. CONCLUSIONS: Luseogliflozin may suppress cardiac hypertrophy in diabetes by reducing Tgf-ß2 expression in cardiomyocytes via the suppression of NHE-1 activity.


Assuntos
Diabetes Mellitus , Miócitos Cardíacos , Trocador 1 de Sódio-Hidrogênio/metabolismo , Animais , Cardiomegalia/patologia , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Glucose/farmacologia , Humanos , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/farmacologia , Sorbitol/análogos & derivados , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta2/farmacologia
3.
Oxid Med Cell Longev ; 2022: 9205908, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35401934

RESUMO

Myocardial fibrosis refers to the pathological changes of heart structure and morphology caused by various reasons of myocardial damage. It has become an important challenge in the later clinical treatment of acute myocardial infarction/ischemic cardiomyopathy or diabetes complicated with heart failure. Ginseng Dingzhi Decoction (GN), a Chinese herbal medicine, can reduce heart failure and protect cardiomyocytes. We infer that this may be related to the interaction with intestinal microbiota and mitochondrial homeostasis. The regulatory mechanism of GN on gut microbiota and mitochondria has not yet been elucidated. The intestinal microbiota was analyzed by the 16S rRNA gene; the fecal samples were sequenced and statistically analyzed to determine the changes of microbiota in the phenotype of heart failure rats. In addition, GN can regulate the microbial population that increases the proportion of short-chain fatty acids and anti-inflammatory bacteria and reduces the proportion of conditional pathogens to diabetic phenotype. The results suggest that GN may improve myocardial injury by regulating intestinal flora. Our data also show that stress-type heart failure caused by TAC (transverse aortic constriction) is accompanied by severe cardiac hypertrophy, reduced cardiac function, redox imbalance, and mitochondrial dysfunction. However, the use of GN intervention can significantly reduce heart failure and myocardial hypertrophy, improve heart function and improve myocardial damage, and maintain the mitochondrial homeostasis and redox of myocardial cells under high glucose stimulation. Interestingly, through in vitro experiments after TMBIM6 siRNA treatment, the improvement effect of GN on cell damage and the regulation of mitochondrial homeostasis were eliminated. TMBIM6 can indirectly regulate mitophagy and mitochondrial homeostasis to attenuate myocardial damage and confirms the regulatory effect of GN on mitophagy and mitochondrial homeostasis. We further intervened cardiomyocytes in high glucose through metformin (MET) and GN combination therapy. Research data show that MET and GN combination therapy can improve the level of mitophagy and protect cardiomyocytes. Our findings provide novel mechanistic insights for the treatment of diabetes combined with myocardial injury (myocardial fibrosis) and provide a pharmacological basis for the study of the combination of Chinese medicine and conventional diabetes treatment drugs.


Assuntos
Cardiomiopatias , Microbioma Gastrointestinal , Insuficiência Cardíaca , Panax , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Cardiomegalia/patologia , Cardiomiopatias/metabolismo , Fibrose , Glucose/metabolismo , Insuficiência Cardíaca/patologia , Medicina Tradicional Chinesa , Proteínas de Membrana/metabolismo , Mitocôndrias , Miócitos Cardíacos/metabolismo , RNA Ribossômico 16S/genética , Ratos
4.
Zhonghua Xin Xue Guan Bing Za Zhi ; 50(4): 361-368, 2022 Apr 24.
Artigo em Chinês | MEDLINE | ID: mdl-35399032

RESUMO

Objective: To investigate the representability and etiological diagnostic value of myocardium samples obtained from patients with hypertrophic cardiomyopathy (HCM) by transthoracic echocardiography-guided percutaneous intramyocardial septal biopsy (myocardial biopsy of Liwen procedure). Methods: This study was a retrospective case-series analysis. Patients with HCM, who underwent myocardial biopsy of Liwen procedure and radiofrequency ablation in Xijing Hospital, Air Force Military Medical University from July to December 2019, were included. Demographic data (age, sex), echocardiographic data and complications were collected through electronic medical record system. The histological and echocardiographic features, pathological characteristics of the biopsied myocardium of the patients were analyzed. Results: A total of 21 patients (aged (51.2±14.5) years and 13 males (61.9%)) were enrolled. The thickness of ventricular septum was (23.3±4.5)mm and the left ventricular outflow tract gradient was (78.8±42.6)mmHg (1 mmHg=0.133 kPa). Eight patients (38.1%) were complicated with hypertension, 1 patient (4.8%) had diabetes, and 2 patients (9.5%) had atrial fibrillation. Hematoxylin-eosin staining of myocardial samples of HCM patients before radiofrequency ablation evidenced myocytes hypertrophy, myocytes disarray, nuclear hyperchromatism, hypertrophy, atypia, coronary microvessel abnormalities, adipocyte infiltration, inflammatory cell infiltration, cytoplasmic vacuoles, lipofuscin deposition. Interstitial fibrosis and replacement fibrosis were detected in Masson stained biopsy samples. Hematoxylin-eosin staining of myocardial samples of HCM patients after radiofrequency ablation showed significantly reduced myocytes, cracked nuclear in myocytes, coagulative necrosis, border disappearance and nuclear fragmentation. Quantitative analysis of myocardial specimens of HCM patients before radiofrequency ablation showed that there were 9 cases (42.9%) with mild myocardial hypertrophy and 12 cases (57.1%) with severe myocardial hypertrophy. Mild, moderate and severe fibrosis were 5 (23.8%), 9 (42.9%) and 7 (33.3%), respectively. Six cases (28.6%) had myocytes disarray. There were 11 cases (52.4%) of coronary microvessel abnormalities, 4 cases (19.0%) of adipocyte infiltration, 2 cases (9.5%) of inflammatory cell infiltration,6 cases (28.5%) of cytoplasmic vacuole, 16 cases (76.2%) of lipofuscin deposition. The diameter of cardiac myocytes was (25.2±2.8)µm, and the percentage of collagen fiber area was 5.2%(3.0%, 14.6%). One patient had severe replacement fibrosis in the myocardium, with a fibrotic area of 67.0%. The rest of the patients had interstitial fibrosis. The myocardial specimens of 13 patients were examined by transmission electron microscopy. All showed increased myofibrils, and 9 cases had disorder of myofibrils. All patients had irregular shape of myocardial nucleus, partial depression, mild mitochondrial swelling, fracture and reduction of mitochondrial crest, and local aggregation of myofibrillary interfascicles. One patient had hypertrophy of cardiomyocytes, but the arrangement of muscle fibers was roughly normal. There were vacuoles in the cytoplasm, and Periodic acid-Schiff staining was positive. Transmission electron microscopy showed large range of glycogen deposition in the cytoplasm, with occasional double membrane surround, which was highly indicative of glycogen storage disease. No deposition of glycolipid substance in lysozyme was observed under transmission electron microscope in all myocardial specimens, which could basically eliminate Fabry disease. No apple green substance was found under polarized light after Congo red staining, which could basically exclude cardiac amyloidosis. Conclusion: Myocardium biopsied samples obtained by Liwen procedure of HCM patients are representative and helpful for the etiological diagnosis of HCM.


Assuntos
Cardiomiopatia Hipertrófica , Cardiopatias Congênitas , Biópsia/efeitos adversos , Cardiomegalia/complicações , Cardiomegalia/patologia , Cardiomiopatia Hipertrófica/diagnóstico , Amarelo de Eosina-(YS) , Fibrose , Hematoxilina , Humanos , Lipofuscina , Masculino , Miocárdio/patologia , Estudos Retrospectivos
5.
Arch Biochem Biophys ; 723: 109217, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35427576

RESUMO

BACKGROUND: To investigate the mechanisms of potential cardioprotective effects of epigallocatechin-3-gallate (EGCG) in pressure overload-induced cardiac dysfunction. METHODS: A chronic heart failure model was established using abdominal aortic constriction (AAC) surgery, rats were divided into sham, AAC, and AAC + EGCG groups. Echocardiography and tissue section staining were performed to evaluate cardiac function and pathology, respectively. Gene expression level were detected with quantitative real-time polymerase chain reactions. Label-free quantitative proteomics was used to investigate the whole proteomes of heart, and the differentially expressed proteins were analyzed using bioinformatics methods. Western blot was performed to validate the levels and the reliability of the differential proteins. RESULTS: Compared with the AAC group, systolic dysfunction was improved in AAC + EGCG group after EGCG treatment. EGCG inhibited myocardial fibrosis and cardiac hypertrophy after AAC, along with reducing atrial natriuretic protein, B-type natriuretic peptide, collagen types 1 and 3 alpha 1, and transforming growth factor ß-1. Quantitative proteomics identified a total of 162 differentially expressed proteins, among them, 18 were closely related to cardiovascular disorders. Bioinformatics analyses showed that EGCG played a therapeutic role mainly by changing energy metabolism processes, such as oxidative phosphorylation and lipid metabolism. Furthermore, NADH: ubiquinone oxidoreductase subunit S4, an important component of the mitochondrial respiratory chain, was increased after AAC and then reversed by EGCG, which was consistent with the proteomics results. CONCLUSIONS: EGCG may correct cardiac systolic dysfunction and prevent cardiac remodeling after heart failure via enhancing the energy metabolism, which provides us with new insights into cardioprotective effects of EGCG related to the energy metabolisms in pressure overload-induced cardiac dysfunction.


Assuntos
Catequina , Insuficiência Cardíaca , Animais , Cardiomegalia/patologia , Catequina/análogos & derivados , Catequina/metabolismo , Catequina/farmacologia , Catequina/uso terapêutico , Modelos Animais de Doenças , Metabolismo Energético , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Ratos , Reprodutibilidade dos Testes
6.
Clin Transl Med ; 12(4): e574, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35390228

RESUMO

AIMS: Senescence-associated pathological cardiac hypertrophy (SA-PCH) is associated with upregulation of foetal genes, fibrosis, senescence-associated secretory phenotype (SASP), cardiac dysfunction and increased morbidity and mortality. Therefore, we conducted experiments to investigate whether GATA4 accumulation induces SA-PCH, and whether Bmi-1-RING1B promotes GATA4 ubiquitination and its selective autophagic degradation to prevent SA-PCH. METHODS AND RESULTS: Bmi-1-deficient (Bmi-1-/- ), transgenic Bmi-1 overexpressing (Bmi-1Tg ) and wild-type (WT) mice were infused with angiotensin II (Ang II) to stimulate the development of SA-PCH. Through bioinformatics analysis with RNA sequencing data from cardiac tissues, we found that Bmi-1-RING1B and autophagy are negatively related to SA-PCH. Bmi-1 deficiency promoted GATA4-dependent SA-PCH by increasing GATA4 protein and hypertrophy-related molecules transcribed by GATA4 such as ANP and BNP. Bmi-1 deficiency stimulated NF-κB-p65-dependent SASP, leading to cardiac dysfunction, cardiomyocyte hypertrophy and senescence. Bmi-1 overexpression repressed GATA4-dependent SA-PCH. GATA4 degraded by Bmi-1 was mainly dependent on autophagy rather than proteasome. In human myocardium, p16 positively correlated with ANP and GATA4 and negatively correlated with LC3B, Bmi-1 and RING1B; GATA4 positively correlated with p62 and negatively correlated with Bmi-1 and LC3B. With increased p16 protein levels, ANP-, BNP- and GATA4-positive cells or areas increased; however, LC3B-positive cells or areas decreased in human myocardium. GATA4 is ubiquitinated after combining with Bmi-1-RING1B, which is then recognised by p62, is translocated to autophagosomes to form autophagolysosomes and degraded. Downregulated GATA4 ameliorated SA-PCH and cardiac dysfunction by reducing GATA4-dependent hypertrophy and SASP-related molecules. Bmi-1 combined with RING1B (residues 1-179) and C-terminus of GATA4 (residues 206-443 including zinc finger domains) through residues 1-95, including a RING-HC-finger. RING1B combined with C-terminus of GATA4 through the C-terminus (residues 180-336). Adeno-associated viral vector serotype 9 (AAV9)-cytomegalovirus (CMV)-Bmi-1-RING1B treatment significantly attenuated GATA4-dependent SA-PCH through promoting GATA4 autophagic degradation. CONCLUSIONS: Bmi-1-RING1B maintained cardiac function and prevented SA-PCH by promoting selective autophagy for degrading GATA4. TRANSLATIONAL PERSPECTIVE: AAV9-CMV-Bmi-1-RING1B could be used for translational gene therapy to ubiquitinate GATA4 and prevent GATA4-dependent SA-PCH. Also, the combined domains between Bmi-1-RING1B and GATA4 in aging cardiomyocytes could be therapeutic targets for identifying stapled peptides in clinical applications to promote the combination of Bmi-1-RING1B with GATA4 and the ubiquitination of GATA4 to prevent SA-PCH and heart failure. We found that degradation of cardiac GATA4 by Bmi-1 was mainly dependent on autophagy rather than proteasome, and autophagy agonists metformin and rapamycin could ameliorate the SA-PCH, suggesting that activation of autophagy with metformin or rapamycin could also be a promising method to prevent SA-PCH.


Assuntos
Cardiomegalia , Infecções por Citomegalovirus , Fator de Transcrição GATA4 , Animais , Fator Natriurético Atrial/metabolismo , Autofagia/genética , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/patologia , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo , Metformina/farmacologia , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Complexo Repressor Polycomb 1 , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas , Sirolimo/metabolismo , Ubiquitina-Proteína Ligases
7.
Oxid Med Cell Longev ; 2022: 5490553, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35464769

RESUMO

Receptor-interacting protein 3(RIP3), a RIP family member, has been reported as a critical regulator of necroptosis and involves in the pathogenesis of various heart diseases. However, its role in the development of myocardial hypertrophy after pressure overload is unclear. We aimed to investigate the roles of RIP3 in pathological cardiac hypertrophy. A rat model of myocardial hypertrophy induced by the aortic banding method was used in this study. Neonatal rat cardiomyocytes (NRCMs) were stimulated with angiotensin II (Ang-II) or phenylephrine (PE) to induce neurohumoral stress. Our results showed that RIP3 level was significantly elevated in the hypertrophic myocardium tissues from patients, rats subjected to AB surgery, and NRCMs treated with Ang-II or PE. After downregulation of RIP3 expression in NRCMs, the phenotypes of myocardial hypertrophy were obviously alleviated. In mechanism, we demonstrated that RIP3 interacts with mixed lineage kinase domain-like protein (MLKL) and promotes its cell membrane localization to increase the influx of calcium within cells, thereby mediating the development of myocardial hypertrophy. More interestingly, we found the blockage of calcium influx by 2-aminoethoxydiphenyl borate, and lanthanum chloride efficiently reverses RIP3-induced cardiac remodeling in NRCMs. Taken together, our findings indicate a key role of the RIP3-MLKL signaling pathway in myocardial hypertrophy, which may be a novel promising treatment strategy for myocardial hypertrophy.


Assuntos
Cálcio , Proteínas Quinases , Animais , Cálcio/metabolismo , Cardiomegalia/patologia , Humanos , Miócitos Cardíacos/metabolismo , Necroptose , Proteínas Quinases/metabolismo , Ratos , Proteína Serina-Treonina Quinases de Interação com Receptores
8.
J Ethnopharmacol ; 291: 115156, 2022 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-35245628

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: LongShengZhi capsule (LSZ), a traditional Chinese medicine, is used for treatment of patients with vascular diseases. LSZ reduced doxorubicin-induced heart failure by reducing production of reactive oxygen species and inhibiting inflammation and apoptosis. AIM OF THE STUDY: This study was to explore whether LSZ could alleviate cardiac remodeling via upregulation of microRNA (miR)-150-5p and the downstream target. Cardiac remodeling was induced by Ang II in vivo and in vitro. RESULTS: LSZ attenuated Ang II-induced cardiac hypertrophy and fibrosis in rats, and in primary cardiomyocytes (CMs) and primary cardiac fibroblasts (CFs). MiR-150-5p was downregulated in Ang II-induced rat heart, CMs and CFs, and these decreases were reserved by LSZ. In vivo overexpression of miR-150-5p by transfection of miR-150-5p agomiR protected Ang II-induced cardiac hypertrophy and fibrosis in rats. Meanwhile, its overexpression also reversed Ang II-induced upregulation of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and ß-myosin heavy chain (ß-MHC) in rat hearts and primary CMs, as well as upregulation of collagen I, collagen III and transforming growth factor-ß (TGF-ß) in rat hearts and primary CFs. Matrix metalloproteinase 14 (MMP14) was validated as the target gene of miR-150-5p, which was overexpressed in Ang II-induced rat heart, rat primary CMs and primary CFs. Notably, overexpression of MMP14 induced cardiac remodeling, and reversed the protective role of miR-150-5p in downregulating Ang II-induced upregulation of hypertrophy and fibrosis markers in vitro. CONCLUSION: Collectively, LSZ protects Ang II-induced cardiac dysfunction and remodeling via upregulation of miR-150-5p to target MMP14. Administration of LSZ, upregulation of miR-150-5p or targeting of MMP14 may be strategies for cardiac remodeling therapy.


Assuntos
Medicamentos de Ervas Chinesas , Metaloproteinase 14 da Matriz , MicroRNAs , Remodelação Ventricular , Angiotensina II/farmacologia , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Fibrose , Metaloproteinase 14 da Matriz/genética , MicroRNAs/genética , Miócitos Cardíacos , Ratos , Regulação para Cima , Remodelação Ventricular/efeitos dos fármacos
9.
Chem Biol Interact ; 358: 109902, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35305975

RESUMO

The up-regulation of Wnt/ß-catenin pathway induces cardiac function abnormalities, hypertrophy, and fibrosis in diabetic hypertensive and pressure overload models. The present study investigates the cardioprotective effects of Wnt/ß-catenin inhibition on isoproterenol (ISO) induced cardiotoxicity in rats. ISO was administered at a dose of 85 mg/kg (s.c) for 2 days. Wnt/ß-catenin inhibitor pyrvinium (60 µg/kg, p.o) was given 2h prior and glibenclamide at a dose of 5 mg/kg; p.o, 2 h after ISO injection. Cardiac function parameters were assessed on isolated hearts by using automated Biopac apparatus. The ß-catenin transcription and expression was detected by RT-PCR technique and immunohistochemical method. Serum and cardiac tissue biochemical changes including cardiac troponin-I, CK-MB, LDH, anti-oxidant enzyme levels, inflammatory cytokines, and membrane associated Na+/K + ATPase and Ca2+ATPase and caspase-3 activity, collagen content, fibronectin protein levels were evaluated in various study groups. Histological studies were also carried out to analyze the cardiomyocyte damage, hypertrophy, fibrosis, and necrosis, while α-SMA, TGF-ß expression was checked by immunostaining. ISO administration enhanced ß-catenin gene expression and transcription which promoted oxidative and nitrosative stress, inflammatory cytokine release, reduced ATP levels, induced over-expression of fibrotic proteins resulting in cardiac hypertrophy, myocardial necrosis, functional and histological changes. However, antagonism of Wnt/ß-catenin pathway attenuated these ISO induced pathological manifestations. Notably, the co-treatment with ATP-sensitive K+ channel inhibitor partially, reduced the cardioprotective effects of Wnt/ß-catenin blocker pyrvinium in ISO rats. Thus Wnt/ß-catenin inhibition exhibits cardioprotective in ISO model by anti-oxidant, anti-inflammatory, anti-fibrotic properties and by possible involvement of ATP-sensitive potassium channel activation.


Assuntos
Cardiotoxicidade , beta Catenina , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Cardiomegalia/patologia , Cardiotoxicidade/metabolismo , Citocinas/metabolismo , Fibrose , Isoproterenol/toxicidade , Miócitos Cardíacos/metabolismo , Necrose/metabolismo , Compostos de Pirvínio , Ratos , beta Catenina/metabolismo
10.
Arch Biochem Biophys ; 722: 109198, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35358489

RESUMO

Cardiac disease is one of the most common complications associated with diabetes. Cardiac hypertrophy and fibrosis often lead to structural and functional abnormalities leading to risks of heart failure. Several regulatory molecules related to major signaling pathways have been found to overexpress in different tissues during diabetes which show very low level of expression in non-diabetic condition. YAP1 and FOXM1 are recently being reported to play important role in various hypertrophic and fibrotic disorders. But, very limited information is still known regarding their roles in cardiomyopathies especially in the context of diabetes and hyperglycemic stress. YAP1 is known to be associated with AKT- GSK3ß signaling that is one of the important regulatory pathways in glucose and lipid metabolism. On the other hand, the expression of FOXM1 has been found to be significantly upregulated in adult lung tissue with induction of fibrosis but little is known about their role in cardiac diseases. In our study, YAP1 and FOXM1 have been found to overexpress in cardiac tissue under hyperglycemic condition leading to cardiomyocyte hypertrophy and increased fibrotic response. Further YAP1 inhibition has resulted in a reduced expression of FOXM1 pointing to a possible association of YAP1 and FOXM1 in high glucose-stressed cardiomyocyte. As mechanism we have found that YAP1 undergoes reduced ser127 phosphorylation as well as extensive O-GlcNAcylation mediated activation under hyperglycemia. Upregulated YAP1 further acts through increased AKT phosphorylation causing inhibition of GSK3ß that in turn results in increased FOXM1 expression, leading to cardiomyocyte hypertrophy and fibrosis.


Assuntos
Hiperglicemia , Proteínas Proto-Oncogênicas c-akt , Cardiomegalia/patologia , Fibrose , Proteína Forkhead Box M1/metabolismo , Glucose/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Hiperglicemia/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
11.
Cancer Res ; 82(9): 1753-1761, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35260887

RESUMO

Heart failure and cancer are the leading cause of deaths worldwide. While heart failure and cancer have been considered separate diseases, it is becoming evident that they are highly connected and affect each other's outcomes. Recent studies using experimental mouse models have suggested that heart failure promotes tumor progression. The mouse models used involve major irreversible surgery. Here, we induced heart hypertrophy via expression of activating transcription factor 3 (ATF3) in cardiomyocytes, followed by cancer cells' implantation. Tumors developing in ATF3-transgenic mice grew larger and displayed a more highly metastatic phenotype compared with tumors in wild-type mice. To address whether ATF3 expression or the cardiac outcome are necessary for tumor progression, ATF3 expression was turned off after cardiac hypertrophy development followed by cancer cell implantation. The tumor promotion phenotype and the enhancement of metastatic properties were preserved, suggesting that the failing heart per se is sufficient to promote tumor progression. Serum derived from ATF3-transgenic mice enhanced cancer cell proliferation and increased cancer cell metastatic properties in vitro. Using a cytokine array panel, multiple factors responsible for promoting tumor cell proliferation and the metastatic phenotype were identified. Interestingly, the failing heart and the tumor separately and simultaneously contributed to higher levels of these factors in the serum as well as other tissues and organs. These data suggest the existence of intimate cross-talk between the hypertrophied heart and the tumor that is mediated by secreted factors, leading to cancer promotion and disease deterioration. SIGNIFICANCE: This work highlights the importance of early diagnosis and treatment of heart failure prior to reaching the irreversible stage that can exacerbate cancer progression.


Assuntos
Insuficiência Cardíaca , Neoplasias , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/metabolismo , Animais , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias/complicações , Remodelação Ventricular
12.
Bioengineered ; 13(4): 8323-8333, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35311628

RESUMO

Tripartite motif-containing 27 (Trim27) is highly expressed in tumor cells and regulates natural immunity and apoptosis. However, the effects of Trim27 in cardiac hypertrophy are not fully elucidated. In this study, we tried to explore the potential role of Trim27 in pressure overload-induced cardiac hypertrophy and the underlying mechanism. The results indicated that compared to sham operation (Sham) group, transverse aortic constriction (TAC) group showed significantly up-regulated Trim27 protein expression (P < 0.05). The neonatal rat cardiomyocytes (NRCMs) were isolated and stimulated with PBS, angiotensin (AngII) and phenylephrine (PE). NRCMs were collected to detect the protein expression of Trim27. The results were consistent with the results in vivo. Compared to PBS treatment, the expression of Trim27 protein in NRCMs was significantly increased after PE or AngII stimulation (P < 0.05, respectively). Knockout of Trim27 can reduce the size of cardiomyocytes and reduce the proteins expression of ANP, BNP, and ß-MHC, improve cardiac function, and reverse myocardial hypertrophy (P < 0.05). Trim27 may be involved in regulating the development of cardiac hypertrophy. Further results showed that Trim27 can increase the protein expression of phosphorylation of Akt, GSK3ß, mTOR, and P70s6k by interacting with PTEN (phosphatase tensin homolog). These findings revealed that Trim27 can promote cardiac hypertrophy by activating PTEN/Akt/GSK3ß/mTOR signaling pathway.


Assuntos
Cardiomegalia , Proteínas de Ligação a DNA , Transdução de Sinais , Animais , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Proteínas de Ligação a DNA/genética , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio Sintase Quinase 3 beta/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
13.
Oxid Med Cell Longev ; 2022: 5044046, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35222798

RESUMO

Cardiac lymphatic vessel growth (lymphangiogenesis) and integrity play an essential role in maintaining tissue fluid balance. Inhibition of lymphatic lymphangiogenesis is involved in cardiac edema and cardiac remodeling after ischemic injury or pressure overload. However, whether lymphatic vessel integrity is disrupted during angiotensin II- (Ang II-) induced cardiac remodeling remains to be investigated. In this study, cardiac remodeling models were established by Ang II (1000 ng/kg/min) in VEGFR-3 knockdown (Lyve-1Cre VEGFR-3f/-) and wild-type (VEGFR-3f/f) littermates. Our results indicated that Ang II infusion not only induced cardiac lymphangiogenesis and upregulation of VEGF-C and VEGFR-3 expression in the time-dependent manner but also enhanced proteasome activity, MKP5 and VE-cadherin degradation, p38 MAPK activation, and lymphatic vessel hyperpermeability. Moreover, VEGFR-3 knockdown significantly inhibited cardiac lymphangiogenesis in mice, resulting in exacerbation of tissue edema, hypertrophy, fibrosis superoxide production, inflammation, and heart failure (HF). Conversely, administration of epoxomicin (a selective proteasome inhibitor) markedly mitigated Ang II-induced cardiac edema, remodeling, and dysfunction; upregulated MKP5 and VE-cadherin expression; inactivated p38 MAPK; and reduced lymphatic vessel hyperpermeability in WT mice, indicating that inhibition of proteasome activity is required to maintain lymphatic endothelial cell (LEC) integrity. Our results show that both cardiac lymphangiogenesis and lymphatic barrier hyperpermeability are implicated in Ang II-induced adaptive hypertrophic remodeling and dysfunction. Proteasome-mediated hyperpermeability of LEC junctions plays a predominant role in the development of cardiac remodeling. Selective stimulation of lymphangiogenesis or inhibition of proteasome activity may be a potential therapeutic option for treating hypertension-induced cardiac remodeling.


Assuntos
Angiotensina II/metabolismo , Cardiomegalia/metabolismo , Edema Cardíaco/metabolismo , Vasos Linfáticos/metabolismo , Angiotensina II/administração & dosagem , Animais , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Edema Cardíaco/tratamento farmacológico , Edema Cardíaco/patologia , Edema Cardíaco/fisiopatologia , Células Endoteliais/metabolismo , Linfangiogênese/efeitos dos fármacos , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Permeabilidade/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/deficiência , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
14.
Biochem J ; 479(3): 401-424, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-35147166

RESUMO

The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade promotes cardiomyocyte hypertrophy and is cardioprotective, with the three RAF kinases forming a node for signal integration. Our aims were to determine if BRAF is relevant for human heart failure, whether BRAF promotes cardiomyocyte hypertrophy, and if Type 1 RAF inhibitors developed for cancer (that paradoxically activate ERK1/2 at low concentrations: the 'RAF paradox') may have the same effect. BRAF was up-regulated in heart samples from patients with heart failure compared with normal controls. We assessed the effects of activated BRAF in the heart using mice with tamoxifen-activated Cre for cardiomyocyte-specific knock-in of the activating V600E mutation into the endogenous gene. We used echocardiography to measure cardiac dimensions/function. Cardiomyocyte BRAFV600E induced cardiac hypertrophy within 10 d, resulting in increased ejection fraction and fractional shortening over 6 weeks. This was associated with increased cardiomyocyte size without significant fibrosis, consistent with compensated hypertrophy. The experimental Type 1 RAF inhibitor, SB590885, and/or encorafenib (a RAF inhibitor used clinically) increased ERK1/2 phosphorylation in cardiomyocytes, and promoted hypertrophy, consistent with a 'RAF paradox' effect. Both promoted cardiac hypertrophy in mouse hearts in vivo, with increased cardiomyocyte size and no overt fibrosis. In conclusion, BRAF potentially plays an important role in human failing hearts, activation of BRAF is sufficient to induce hypertrophy, and Type 1 RAF inhibitors promote hypertrophy via the 'RAF paradox'. Cardiac hypertrophy resulting from these interventions was not associated with pathological features, suggesting that Type 1 RAF inhibitors may be useful to boost cardiomyocyte function.


Assuntos
Cardiomegalia/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Miócitos Cardíacos/patologia , Proteínas Proto-Oncogênicas B-raf/fisiologia , Animais , Carbamatos/farmacologia , Carbamatos/toxicidade , Cardiomegalia/metabolismo , Tamanho Celular/efeitos dos fármacos , Células Cultivadas , Dimerização , Técnicas de Introdução de Genes , Insuficiência Cardíaca/patologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Mutação Puntual , Conformação Proteica/efeitos dos fármacos , Mapeamento de Interação de Proteínas , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-raf/biossíntese , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Sulfonamidas/toxicidade
15.
Biochem Biophys Res Commun ; 593: 65-72, 2022 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-35063771

RESUMO

Icariin (ICA), a bioactive flavonoid compound derived from Epimedium, have been demonstrated possessing anti-oxidative stress, anti-inflammation in the cardiovascular disease. But its effects on cardiomyocyte hypertrophy and the underlying mechanisms remains unclear. Here we found that ICA alleviated ISO-induced H9c2 or NRCM myocytes hypertrophy, assessed by surface area and the expression of ANP, BNP and ß-MHC. Furthemore, ICA reversed cardiomcytes enlargment by suppresing apoptotic injury and increasing autophagic flux. By contrast, 3-MA, an autophagy inhibitor, could abolished the antihypertrophic and pro-autophagic flux effects of ICA. Mechanistically, ICA increased the phosphorylation levels of AMPK and autophagy-related markers beclin-1, Atg5 and the LC3II/I ratio, and decreased phosphorylated mTOR. But the effects of ICA on ISO-induced cardiomyocytes hypertrophy were attenuated by selective AMPK inhibitor Compound C. In conclusion, these findings indicated that ICA attenuated cardiomyocyte hypertrophy induced by ISO and prevented cell injury, and the specific mechanism was mediated by AMPK/mTOR pathway to enhance autophagy and reduce autophagy-related cardiomyocyte apoptosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia , Cardiomegalia/prevenção & controle , Flavonoides/farmacologia , Isoproterenol/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Animais Recém-Nascidos , Apoptose , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiotônicos/toxicidade , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/genética
16.
Cell Mol Life Sci ; 79(2): 93, 2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-35075545

RESUMO

Arterial hypertension causes left ventricular hypertrophy leading to dilated cardiomyopathy. Following compensatory cardiomyocyte hypertrophy, cardiac dysfunction develops due to loss of cardiomyocytes preceded or paralleled by cardiac fibrosis. Zyxin acts as a mechanotransducer in vascular cells that may promote cardiomyocyte survival. Here, we analyzed cardiac function during experimental hypertension in zyxin knockout (KO) mice. In zyxin KO mice, made hypertensive by way of deoxycorticosterone acetate (DOCA)-salt treatment telemetry recording showed an attenuated rise in systolic blood pressure. Echocardiography indicated a systolic dysfunction, and isolated working heart measurements showed a decrease in systolic elastance. Hearts from hypertensive zyxin KO mice revealed increased apoptosis, fibrosis and an upregulation of active focal adhesion kinase as well as of integrins α5 and ß1. Both interstitial and perivascular fibrosis were even more pronounced in zyxin KO mice exposed to angiotensin II instead of DOCA-salt. Stretched microvascular endothelial cells may release collagen 1α2 and TGF-ß, which is characteristic for the transition to an intermediate mesenchymal phenotype, and thus spur the transformation of cardiac fibroblasts to myofibroblasts resulting in excessive scar tissue formation in the heart of hypertensive zyxin KO mice. While zyxin KO mice per se do not reveal a cardiac phenotype, this is unmasked upon induction of hypertension and owing to enhanced cardiomyocyte apoptosis and excessive fibrosis causes cardiac dysfunction. Zyxin may thus be important for the maintenance of cardiac function in spite of hypertension.


Assuntos
Angiotensina II/toxicidade , Cardiomegalia/prevenção & controle , Fibrose/prevenção & controle , Hipertensão/complicações , Miócitos Cardíacos/citologia , Zixina/fisiologia , Animais , Apoptose , Pressão Sanguínea , Cardiomegalia/etiologia , Cardiomegalia/patologia , Fibrose/etiologia , Fibrose/patologia , Hipertensão/induzido quimicamente , Hipertensão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/metabolismo
17.
J Cardiovasc Pharmacol ; 79(5): 711-718, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35058409

RESUMO

ABSTRACT: The aim of this study was to investigate whether Treg/Th17 ratio regulation plays an important role in epigallocatechin-3-gallate (EGCG) in attenuating increased afterload-induced cardiac hypertrophy. Three-month-old male C57BL/6 mice were divided into sham + vehicle, abdominal aortic constriction (AAC) + vehicle, and AAC + EGCG groups. Intraperitoneal EGCG (50 mg/kg/d) administration was conducted. Cardiac structure and function were examined by ultrasonography. Pathology was examined by hematoxylin and eosin staining, wheat germ agglutinin staining, and Masson's trichome staining. T-lymphocyte subtypes were analyzed using immunofluorescence and flow cytometry assays. Ultrasonography showed that the ventricular wall in the AAC + vehicle group was thicker than that in the sham + vehicle group (P < 0.05). Hematoxylin and eosin staining revealed cardiomyocyte hypertrophy accompanied by a small amount of inflammatory cell infiltration in the AAC + vehicle group. The results of wheat germ agglutinin staining demonstrated the presence of hypertrophic cardiomyocytes in the AAC + vehicle group (P < 0.01). Masson's trichome staining showed cardiac fibrosis in the AAC + vehicle group, and the immunofluorescence assay revealed infiltration of CD4+ cells in both AAC + vehicle and AAC + EGCG groups. Splenic flow cytometry showed a significant increase in the proportion of Treg cells in the AAC + EGCG group (P < 0.05). The proportion of Th17 cells in the AAC + vehicle group was significantly higher than that in the sham + vehicle group (P < 0.05). In conclusion, changes in the Treg/Th17 ratio are associated with the occurrence of myocardial hypertrophy caused by increased afterload. Moreover, regulation of the Treg/Th17 ratio by EGCG may play an important role in the attenuation of myocardial hypertrophy.


Assuntos
Linfócitos T Reguladores , Células Th17 , Animais , Cardiomegalia/patologia , Catequina/análogos & derivados , Modelos Animais de Doenças , Amarelo de Eosina-(YS) , Hematoxilina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Aglutininas do Germe de Trigo
18.
Exp Cell Res ; 410(1): 112954, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34856161

RESUMO

The RING-domain E3 ubiquitin ligase RNF146 is an enzyme that plays an important role in ubiquitin-proteasomal protein degradation and participates in various pathophysiological processes. However, its role in cardiac hypertrophy is unclear. In the present work, thoracic transverse aortic constriction (TAC) was performed in transgenic mice with RNF146 knockout mice (KO) and wild-type mice, and neonatal rat cardiomyocytes (NRCMs) were subjected to angiotensin II (Ang II) stimulation to induce cardiac hypertrophy in vitro and in vivo. RNF146 expression was significantly increased in hypertrophied murine hearts and Ang II-stimulated NRCMs. RNF146-KO mice and knockdown of RNF146 NRCMs attenuated TAC- or Ang II-stimulated cardiac hypertrophy. Conversely, enforced expression of RNF146 aggravated these changes. Mechanistically, we found that RNF146 KO or knockdown increased the activation of the AMP-activated protein kinase (AMPK) pathway. Furthermore, we found that RNF146 KO or knockdown decreased ubiquitination of Liver kinase B1 (LKB1), which promoted the activation of the AMPK pathway in a dependent manner. In conclusion, RNF146 targets LKB1 protein for ubiquitin-proteasome degradation in cardiomyocytes and subsequently promotes cardiac hypertrophy by suppressing the activation of the AMPK signaling pathway.


Assuntos
/genética , Proteínas Quinases Ativadas por AMP/genética , Cardiomegalia/genética , Ubiquitina-Proteína Ligases/genética , Animais , Cardiomegalia/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteólise , Ratos , Transdução de Sinais/genética
19.
Life Sci ; 288: 120159, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34801516

RESUMO

AIMS: Pathological cardiac hypertrophy is a characteristic feature in many cardiovascular diseases (CVDs). Aloin is an anthraquinone glycoside from Aloe species, and the effect of aloin on cardiac hypertrophy and associated fibrotic changes have not been elucidated. This study investigated the effect of aloin against the isoproterenol (ISO)-induced cardiac hypertrophy in rats. MAIN METHODS: Cardiac hypertrophy experimental model was induced in rats by subcutaneous injection of ISO for 14 days. Meanwhile, the animals were administered orally with aloin at doses of 25 and 50 mg/kg/day. On the 15th day, cardiac echocardiography was performed, the heart was collected and subjected for histopathological, gene expression, and immunoblot studies. Additionally, the effect of aloin on ISO-induced hypertrophic changes in H9c2 cells was investigated. KEY FINDINGS: Aloin markedly alleviated ISO-induced heart injury, reduced cardiac hypertrophy, improved cardiac function, and histological alterations in the heart. Mechanistically, aloin attenuated ISO-induced fibrosis via inhibition of the levels of collagen I, α-smooth muscle actin (α-SMA), fibronectin, transforming growth factor-ß (TGF-ß) and pSmad2/3 proteins in the heart. Aloin alleviated ISO-induced myocardial oxidative damage and up-regulated the levels of antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins. Moreover, aloin treatment attenuated ISO-induced hypertrophic changes and the generation of reactive oxygen species (ROS) in H9c2 cells in vitro. SIGNIFICANCE: Our findings demonstrated that aloin alleviated ISO-induced cardiac hypertrophy and fibrosis via inhibiting TGF-ß/pSmad2/3 signaling and restoring myocardial antioxidants, and therefore has promising therapeutic potential against cardiac hypertrophy and fibrosis.


Assuntos
Antioxidantes/farmacologia , Cardiomegalia/prevenção & controle , Emodina/análogos & derivados , Fibrose/prevenção & controle , Estresse Oxidativo , Agonistas Adrenérgicos beta/toxicidade , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Catárticos/farmacologia , Emodina/farmacologia , Fibrose/induzido quimicamente , Fibrose/metabolismo , Fibrose/patologia , Isoproterenol/toxicidade , Masculino , Oxirredução , Ratos , Ratos Sprague-Dawley
20.
Acta Pharmacol Sin ; 43(1): 50-63, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33785860

RESUMO

Harmine is a ß-carboline alkaloid isolated from Banisteria caapi and Peganum harmala L with various pharmacological activities, including antioxidant, anti-inflammatory, antitumor, anti-depressant, and anti-leishmanial capabilities. Nevertheless, the pharmacological effect of harmine on cardiomyocytes and heart muscle has not been reported. Here we found a protective effect of harmine on cardiac hypertrophy in spontaneously hypertensive rats in vivo. Further, harmine could inhibit the phenotypes of norepinephrine-induced hypertrophy in human embryonic stem cell-derived cardiomyocytes in vitro. It reduced the enlarged cell surface area, reversed the increased calcium handling and contractility, and downregulated expression of hypertrophy-related genes in norepinephrine-induced hypertrophy of human cardiomyocytes derived from embryonic stem cells. We further showed that one of the potential underlying mechanism by which harmine alleviates cardiac hypertrophy relied on inhibition of NF-κB phosphorylation and the stimulated inflammatory cytokines in pathological ventricular remodeling. Our data suggest that harmine is a promising therapeutic agent for cardiac hypertrophy independent of blood pressure modulation and could be a promising addition of current medications for cardiac hypertrophy.


Assuntos
Cardiomegalia/tratamento farmacológico , Harmina/farmacologia , Substâncias Protetoras/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Administração Oral , Animais , Banisteriopsis/química , Cardiomegalia/induzido quimicamente , Cardiomegalia/patologia , Relação Dose-Resposta a Droga , Harmina/administração & dosagem , Estrutura Molecular , Miócitos Cardíacos/efeitos dos fármacos , Norepinefrina/antagonistas & inibidores , Peganum/química , Substâncias Protetoras/administração & dosagem , Ratos , Ratos Wistar , Bibliotecas de Moléculas Pequenas/administração & dosagem , Relação Estrutura-Atividade
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