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1.
Naunyn Schmiedebergs Arch Pharmacol ; 397(8): 5861-5873, 2024 08.
Article in English | MEDLINE | ID: mdl-38334825

ABSTRACT

Recent evidence suggests the mechanistic role of mitochondria and oxidative stress in the development of celecoxib-induced cardiotoxicity. On the other, it has reported the positive effects of vitamin D on oxidative stress and the maintenance of mitochondrial functions. This current study examined the cardiac effects of celecoxib, doxorubicin, vitamin D, and a combination of them in rats. The effect of 10 days of celecoxib (100 mg/kg/day), doxorubicin (2.5 mg/kg), vitamin D (60,000 U/kg), and their combination was studied on cardiac function according to serum lactate dehydrogenase (LDH), creatine kinase (CK), glutathione (GSH), and malondialdehyde (MDA) levels as well as mitochondrial succinate dehydrogenases (SDH) activity, reactive oxygen species (ROS) production, mitochondrial swelling, and mitochondrial membrane potential (MMP). Results showed that celecoxib and its combination with doxorubicin led to abnormality in paws and limbs, increased pressure in the eyes, blindness and animal death (in about 75% of the animals under study). Moreover, celecoxib and its combination with doxorubicin significantly increased cardiotoxicity biomarkers, oxidative stress markers (GSH and MDA), and mitochondrial toxicity parameters (SDH, ROS formation, MMP collapse, mitochondrial swelling). However, the combination of vitamin D with celecoxib and celecoxib + doxorubicin caused a significant reversal of deformity in paws and limbs, increased pressure in the eye, blindness, and animal death, as well as cardiotoxicity, oxidative stress, and mitochondrial parameters. This study proved for the first time the beneficial effect of vitamin D on celecoxib-induced cardiotoxicity, which is aggravated in the presence of doxorubicin through the maintenance of mitochondrial functions and its antioxidant potential.


Subject(s)
Antioxidants , Cardiotoxicity , Celecoxib , Disease Models, Animal , Doxorubicin , Heart Failure , Mitochondria, Heart , Oxidative Stress , Rats, Wistar , Vitamin D , Animals , Doxorubicin/toxicity , Celecoxib/pharmacology , Antioxidants/pharmacology , Male , Oxidative Stress/drug effects , Cardiotoxicity/metabolism , Vitamin D/pharmacology , Mitochondria, Heart/drug effects , Mitochondria, Heart/metabolism , Heart Failure/chemically induced , Heart Failure/metabolism , Heart Failure/drug therapy , Rats , Reactive Oxygen Species/metabolism , Membrane Potential, Mitochondrial/drug effects
2.
AIDS ; 38(4): 547-556, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-37967231

ABSTRACT

OBJECTIVES: Heart failure risk is elevated in people with HIV (PWH). We investigated whether initial antiretroviral therapy (ART) regimens influenced heart failure risk. DESIGN: Cohort study. METHODS: PWH who initiated an ART regimen between 2000 and 2016 were identified from three integrated healthcare systems. We evaluated heart failure risk by protease inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTI), and integrase strand transfer inhibitor (INSTI)-based ART, and comparing two common nucleotide reverse transcriptase inhibitors: tenofovir disoproxil fumarate (tenofovir) and abacavir. Follow-up for each pairwise comparison varied (i.e. 7 years for protease inhibitor vs. NNRTI; 5 years for tenofovir vs. abacavir; 2 years for INSTIs vs. PIs or NNRTIs). Hazard ratios were from working logistic marginal structural models, fitted with inverse probability weighting to adjust for demographics, and traditional cardiovascular risk factors. RESULTS: Thirteen thousand six hundred and thirty-four PWH were included (88% men, median 40 years of age; 34% non-Hispanic white, 24% non-Hispanic black, and 24% Hispanic). The hazard ratio (95% CI) were: 2.5 (1.5-4.3) for protease inhibitor vs. NNRTI-based ART (reference); 0.5 (0.2-1.8) for protease inhibitor vs. INSTI-based ART (reference); 0.1 (0.1-0.8) for NNRTI vs. INSTI-based ART (reference); and 1.7 (0.5-5.7) for tenofovir vs. abacavir (reference). In more complex models of cumulative incidence that accounted for possible nonproportional hazards over time, the only remaining finding was evidence of a higher risk of heart failure for protease inhibitor compared with NNRTI-based regimens (1.8 vs. 0.8%; P  = 0.002). CONCLUSION: PWH initiating protease inhibitors may be at higher risk of heart failure compared with those initiating NNRTIs. Future studies with longer follow-up with INSTI-based and other specific ART are warranted.


Subject(s)
Anti-HIV Agents , Cyclopropanes , Dideoxyadenosine/analogs & derivatives , HIV Infections , HIV Protease Inhibitors , Heart Failure , Male , Humans , Female , HIV Infections/complications , HIV Infections/drug therapy , Reverse Transcriptase Inhibitors/adverse effects , Anti-HIV Agents/adverse effects , Cohort Studies , HIV Protease Inhibitors/adverse effects , Dideoxynucleosides/adverse effects , Tenofovir/adverse effects , Heart Failure/chemically induced , Heart Failure/epidemiology , Heart Failure/drug therapy
3.
Clin Sci (Lond) ; 138(1): 23-42, 2024 01 10.
Article in English | MEDLINE | ID: mdl-38060817

ABSTRACT

Reductions in Na+-K+-ATPase (NKA) activity and expression are often observed in the progress of various reason-induced heart failure (HF). However, NKA α1 mutation or knockdown cannot cause spontaneous heart disease. Whether the abnormal NKA α1 directly contributes to HF pathogenesis remains unknown. Here, we challenge NKA α1+/- mice with isoproterenol to evaluate the role of NKA α1 haploinsufficiency in isoproterenol (ISO)-induced cardiac dysfunction. Genetic knockdown of NKA α1 accelerated ISO-induced cardiac cell hypertrophy, heart fibrosis, and dysfunction. Further studies revealed decreased Krebs cycle, fatty acid oxidation, and mitochondrial OXPHOS in the hearts of NKA α1+/- mice challenged with ISO. In ISO-treated conditions, inhibition of NKA elevated cytosolic Na+, further reduced mitochondrial Ca2+ via mNCE, and then finally down-regulated cardiac cell energy metabolism. In addition, a supplement of DRm217 alleviated ISO-induced heart dysfunction, mitigated cardiac remodeling, and improved cytosolic Na+ and Ca2+ elevation and mitochondrial Ca2+ depression in the NKA α1+/- mouse model. The findings suggest that targeting NKA and mitochondria Ca2+ could be a promising strategy in the treatment of heart disease.


Subject(s)
Heart Failure , Myocytes, Cardiac , Mice , Animals , Isoproterenol/metabolism , Isoproterenol/pharmacology , Myocytes, Cardiac/metabolism , Calcium/metabolism , Heart Failure/chemically induced , Heart Failure/genetics , Heart Failure/metabolism , Cardiomegaly/chemically induced , Cardiomegaly/genetics , Cardiomegaly/metabolism , Adenosine Triphosphatases/metabolism
4.
J Pharm Biomed Anal ; 236: 115738, 2023 Nov 30.
Article in English | MEDLINE | ID: mdl-37742504

ABSTRACT

OBJECTIVE: This study aimed to explore the mechanism of total saponin of black ginseng (TSBG) in treating heart failure (HF) in DOX-induced HF model rats. METHODS: Rats with HF induced by the intraperitoneal injection of DOX were treated with TSBG (low dose, 30 mg/kg/day; medium dose, 60 mg/kg/day; high dose, 120 mg/kg/day) and shakubar trivalsartan (80 mg/kg/day, positive control) for four weeks. Serum BNP and ANP levels were tested by ELISA, and pathological tissue sections were examined. Serum metabolites were measured using nontargeted metabolomic techniques. The expression of Akt/mTOR autophagy-associated proteins in heart tissue was detected using Western blot, including Beclin1, p62, LCII and LC3I. RESULTS: Compared with the model group, rats in the TSBG-H group had a significantly lower heart index (p < 0.05), significantly lower serum levels of BNP (p < 0.01) and ANP (p < 0.01) and significantly fewer cardiac histopathological changes. Metabolomic results showed that TSBG significantly back-regulated 12 metabolites (p < 0.05), including cholesterol, histamine, sphinganine, putrescine, arachidonic acid, 3-sulfinoalanine, hypotaurine, gluconic acid and lysoPC (18:0:0). These metabolite changes were involved in taurine and hypotaurine metabolism, arachidonic acid metabolism, sphingolipid metabolism, etc. The protein expression level of p-Akt/Akt and p-mTOR/mTOR was significantly up-regulated (p < 0.001), whereas that of Beclin1, p62 (p < 0.001) and LCII/LC3I was down-regulated (p < 0.05). CONCLUSION: TSBG has an excellent therapeutic effect on DOX-induced HF in rats, probably by regulating the Akt/mTOR autophagy signalling pathway, resulting in the improvement of taurine and hypotaurine metabolism, arachidonic acid metabolism and sphingolipid metabolism, which may provide a reference for elucidating the potential mechanism of action of TSBG against HF.


Subject(s)
Heart Failure , Panax , Saponins , Rats , Animals , Rats, Sprague-Dawley , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/therapeutic use , Saponins/pharmacology , Beclin-1 , Panax/metabolism , Arachidonic Acid , Heart Failure/chemically induced , Heart Failure/drug therapy , TOR Serine-Threonine Kinases/metabolism , Metabolomics , Taurine , Sphingolipids/therapeutic use
5.
Am J Cardiol ; 204: 360-365, 2023 10 01.
Article in English | MEDLINE | ID: mdl-37573615

ABSTRACT

Randomized controlled trials have demonstrated mortality benefits for several medication classes in patients with heart failure (HF), especially with reduced ejection fraction (EF). However, the benefit of these traditional HF therapies in patients with HF from cardiac amyloidosis is unclear. our study aimed to evaluate the safety and efficacy of traditional HF therapies in patients with cardiac amyloidosis and HF with reduced EF or HF with mid-range EF (HFmrEF). We conducted a single-center retrospective study. Patients were included if they were diagnosed with cardiac amyloidosis and HF with reduced EF or HF with mid-range EF between January 2012 and 2022. The primary outcomes of interest were medication use patterns (for ß blockers [BB], angiotensin-converting enzyme inhibitors [ACEI], angiotensin receptor blockers [ARBs], angiotensin receptor neprilysin inhibitors [ARNI], and mineralocorticoid receptor antagonists [MRAs]); potential medication side effects (symptomatic bradycardia, fatigue, hypotension, lightheadedness, and syncope); hospitalization; and death. The associations of BB, ACEI/ARB/ARNI, and MRA use with clinical outcomes were evaluated using Kaplan-Meier and Cox proportional hazards regression. A total of 82 patients met study criteria. At time of cardiac amyloidosis diagnosis, 63.4% were on a BB, 51.2% were on an ACEI/ARB/ARNI, and 43.9% were on an MRA. At last follow-up, 51.2% were on a BB, 35.4% were on an ACEI/ARB/ARNI, and 43.9% were on an MRA. There were no statistically significant differences in rates of potential medication side effects in patients on the medication class compared with those who were not. There was no association with hospitalization or mortality for baseline or follow-up BB, ACEI/ARB/ARNI, or MRA use. In conclusion, BBs, ACEI/ARB/ARNIs, and MRAs may be safely used in this population. However, their use does not appear to improve mortality or hospitalization.


Subject(s)
Heart Failure , Ventricular Dysfunction, Left , Humans , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Angiotensin Receptor Antagonists/adverse effects , Retrospective Studies , Stroke Volume , Heart Failure/complications , Heart Failure/drug therapy , Heart Failure/chemically induced , Ventricular Dysfunction, Left/chemically induced , Adrenergic beta-Antagonists/therapeutic use , Adrenergic beta-Antagonists/pharmacology , Mineralocorticoid Receptor Antagonists/therapeutic use , Mineralocorticoid Receptor Antagonists/pharmacology
6.
Comb Chem High Throughput Screen ; 26(14): 2502-2516, 2023.
Article in English | MEDLINE | ID: mdl-37056062

ABSTRACT

BACKGROUND: Doxorubicin-induced heart failure is a clinical problem that needs to be solved urgently. Previous studies have confirmed that Zhenwu Decoction, a traditional Chinese medicine compound, can effectively improve chronic heart failure. However, its interventional effect on Doxorubicin-induced heart failure has not yet been investigated. In this study, we investigated the therapeutic effect and potential mechanism of Zhenwu Decoction on Doxorubicininduced heart failure through animal experiments and network pharmacology. OBJECTIVE: The study aimed to investigate the therapeutic effect and potential mechanism of Zhenwu Decoction (ZWD) on Doxorubicin-induced heart failure. METHODS: A heart-failure mouse model was established in 8-week-old male C57/BL6J mice using Doxorubicin, and the mice were then treated with ZWD for a 4-week period. Firstly, network pharmacology was conducted to explore the potential active components and molecular mechanisms of ZWD on Doxorubicin-induced heart failure. Next, we conducted an in vivo study on the effect of ZWD on Doxorubicin-induced heart failure. After the intervention, the cardiac function and levels of cardiac function injury marker in serum were measured to evaluate the therapeutic effect of ZWD on cardiac function. Then HE staining and Masson staining were used to evaluate the effect of ZWD on myocardial pathology, and biochemical method was used to detect the effect of ZWD on total antioxidant capacity and inflammation, and finally, Western blot was used to detect TGFß, Smad-3, and collagen I protein expression levels to evaluate its effect on myocardial fibrosis. RESULTS: In Doxorubicin-induced heart failure mice, ZWD improved cardiac function and reduced the levels of CK-MB, NT-proBNP, and BNP in the serum, improved myocardial pathology, and reduced TGFß, Smad-3 and collagen I protein expression levels to improve myocardial fibrosis. Network pharmacological analysis showed that ZWD has 146 active ingredients and 248 candidate targets. Moreover, 2,809 genes were found to be related to Doxorubicin-induced heart failure, and after screening, 74 common targets were obtained, mainly including IL-6, AKT1, caspase-3, PPARG, PTGS2, JUN, HSP90AA1, and ESR1. KEGG analysis confirmed that PI3K/AKT and IL- 6/NF-κB signaling pathways were the two main pathways underlying the cardioprotective effects of ZWD. Finally, in vivo experiments showed that ZWD improved the total antioxidant capacity, reduced the SOD level, increased the protein expression of PI3K, Akt, Bcl-2, Bax, and caspase-3, reduced the levels of TNF-α, IL-6, and IL-1ß, and decreased the NF-κB p65, IL-6, and TNF-α protein expression levels. CONCLUSION: In Doxorubicin-induced heart-failure mice, Zhenwu Decoction improved the cardiac function and myocardial pathology, and improved myocardial fibrosis through the TGFß/Smad-3 signaling pathway. According to the prediction of network pharmacology, in vivo experiments demonstrated that Zhenwu Decoction can improve the oxidative stress response, improve myocardial cell apoptosis through the PI3K/AKT signaling pathway, and improve myocardial inflammation by reducing the levels of inflammatory factors and by reducing the protein expression of NF- κB p65, IL-6, and TNF-α.


Subject(s)
Drugs, Chinese Herbal , Heart Failure , Male , Mice , Animals , Caspase 3 , NF-kappa B/metabolism , NF-kappa B/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Tumor Necrosis Factor-alpha , Antioxidants/therapeutic use , Interleukin-6 , Phosphatidylinositol 3-Kinases , Network Pharmacology , Heart Failure/chemically induced , Heart Failure/drug therapy , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Doxorubicin/adverse effects , Inflammation/drug therapy , Models, Theoretical , Fibrosis
7.
Phytomedicine ; 112: 154697, 2023 Apr.
Article in English | MEDLINE | ID: mdl-36805482

ABSTRACT

BACKGROUND: Qiangxin recipe (QXF) is a well-known Chinese herbal medicine commonly used in Asia for thousands of years to treat cardiovascular diseases, but its underlying mechanism remains unclear. PURPOSE: This study aimed to illustrate whether Qiangxin Recipe (QXF) induce glucose metabolism and inhibit cardiomyocyte apoptosis by promoting the activation of the transcription factor Krüppel like factor 5 (KLF5). MATERIAL AND METHODS: In vitro experiments, we constructed an H9C2 cardiomyocyte injury model using doxorubicin and used RNA-seq data analysis to detect the mechanism of QXF. In in vivo experiments, C57 BL/6 mice injected with doxorubicin (4 mg/kg every 6 days, for 30 days) to construct a CHF mouse model and randomly divided into to the normal control group, Dox group and Dox+QXF group (2.12 g/kg/day, 4.24 g/kg/day, for 30 days). Using Echocardiography, serum biochemical indices BNP, cTnl; and histopathological tests involving HE staining, Tunel staining and Immuno-dual fluorescence colocalization to analyze the therapeutic mechanism of QXF. RESULTS: We verified that the Qiangxin recipe could reverse cardiomyocyte dying through enhancing glucose metabolism and reducing apoptosis to improve CHF. Mechanistically, we discovered that the Qiangxin recipe promoted the activation of transcription factor Krüppel-like factor 5 (KLF5) to induce glucose metabolism and inhibit apoptosis in cardiomyocytes. Further, we identified that KLF5 increased the promoter activity of hexokinase 2 (HK2) and B-cell CLL/lymphoma 2 (BCL2) genes, which further enhanced glucose metabolism and inhibited apoptosis of cardiomyocytes. CONCLUSIONS: We highlighted the importance of KLF5-mediated signaling pathways in the treatment of CHF as shown by their participation in glucose metabolism and apoptosis in a doxorubicin-induced model of cardiomyocyte injury, as well as show that Qiangxin recipe can be used as a novel targeted therapy for the treatment of CHF. Compared with previous studies, we provide new ideas for the treatment of Doxorubicin-induced CHF from the perspective of energy metabolism.


Subject(s)
Drugs, Chinese Herbal , Heart Failure , Animals , Mice , Apoptosis/genetics , Doxorubicin , Glucose/metabolism , Heart Failure/chemically induced , Heart Failure/drug therapy , Heart Failure/metabolism , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Myocytes, Cardiac/metabolism , Transcription Factors/metabolism
8.
Oxid Med Cell Longev ; 2023: 3271057, 2023.
Article in English | MEDLINE | ID: mdl-36785789

ABSTRACT

Background: The pharmacological mechanism of the traditional Chinese medicine formula-Jijiu Huiyang decoction (JJHYD), which contains several herbal medicines for the treatment of chronic heart failure (CHF), is yet unknown. Method and Materials. The main active components of JJHYD were analyzed by ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS). The target genes of JJHYD and CHF were retrieved through multiple databases, a drug-ingredient-target-disease network was created, and KEGG enrichment and GO analyses were carried out. The binding ability of paeonol and Glycogen Synthase Kinase-3 alpha (GSK3A) was confirmed by molecular docking. CHF animal model and cell model were constructed. The effects of paeonol on cardiac dysfunction, myocardial hypertrophy, cardiac lipid accumulation, and myocardial apoptosis were detected by echocardiography, histopathology, and flow cytometry, respectively. The effects of paeonol on the expression of myocardial hypertrophy index, GSK3A, and genes or proteins related to the PPARα pathway were determined by qRT-PCR or western blot. Result: UHPLC-MS/MS analysis combined with database verification showed a total of 227 chemical components in JJHYD, among which paeonol was the one with heart-protective roles and had the highest content. Paeonol alleviated isoproterenol-induced cardiac lipid accumulation, cardiac hypertrophy, and myocardial dysfunction and inhibited the activation of the PPARα pathway, while overexpression of GSK3A reversed these effects of paeonol. However, the reversal effects of GSK3A overexpression could be offset by siPPARα. Conclusion: As the main active substance of JJHYD, paeonol participates in the protection of CHF by targeting the GSK3A/PPARα signaling pathway to reduce lipid toxicity.


Subject(s)
Drugs, Chinese Herbal , Heart Failure , Animals , Isoproterenol/adverse effects , PPAR alpha/genetics , Molecular Docking Simulation , Tandem Mass Spectrometry , Heart Failure/chemically induced , Heart Failure/drug therapy , Protein Serine-Threonine Kinases , Cardiomegaly/drug therapy , Lipids , Drugs, Chinese Herbal/adverse effects
9.
Phytomedicine ; 109: 154590, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36610170

ABSTRACT

BACKGROUND: Heart failure (HF), caused by stress cardiomyopathy, is a major cause of mortality. Cardiac fibrosis is an essential structural remodeling associated with HF; therefore, preventing cardiac fibrosis is crucial to decelerating the progression of HF. Sodium houttuyfonate (SH), an extract of Houttuynia cordata, has a potent therapeutic effect on hypoxic cardiomyocytes in a myocardial infarction model. PURPOSE: To investigate the preventative and therapeutic effects of SH during isoproterenol (ISO)-induced HF and explore the pharmacological mechanism of SH in alleviating HF. METHODS: We analyzed the overlapping target genes between SH and cardiac fibrosis or HF using a network pharmacology analytical method. We verified the suppressive effect of SH on ISO-induced proliferation and activation of cardiac fibroblasts by immunohistochemical staining and histological analysis in an isoproterenol-induced HF mouse model. Additionally, we investigated the effect of SH by evaluating fibrosis and cardiac remodeling markers. To further decipher the pharmacological mechanism of SH against cardiac fibrosis and HF, we performed a molecular docking analysis between SH and hub common target genes. RESULTS: There were 20 overlapping target genes between SH and cardiac fibrosis and 32 overlapping target genes between SH and HF. The 16 common target genes of SH against cardiac fibrosis and HF included MMP2 (matrix metalloproteinase 2), and p38. SH significantly inhibited the ISO- or TGF-ß-induced expression of Col1α (collagen 1), α-SMA (smooth muscle actin), MMP2, TIMP2 (tissue inhibitor of metalloproteinase 2), TGF-ß (transforming growth factor), and Smad2 phosphorylation. Moreover, both ISO- and TGF-ß-induced p38 phosphorylation was inhibited. Molecular docking analysis showed that SH forms a stable complex with MMP2 and p38. CONCLUSIONS: In addition to protecting cardiomyocytes, SH directly inhibits cardiac fibroblast activation and proliferation by binding to MMP2 and p38, subsequently delaying cardiac fibrosis and HF progression. Our prevention- and intervention-based approaches in this study showed that SH inhibited the development of stress cardiomyopathy-mediated cardiac fibrosis and HF when SH was administered before or after the initiation of cardiac stress.


Subject(s)
Cardiomyopathies , Heart Failure , Takotsubo Cardiomyopathy , Mice , Animals , Matrix Metalloproteinase 2 , Isoproterenol , Tissue Inhibitor of Metalloproteinase-2 , Takotsubo Cardiomyopathy/pathology , Molecular Docking Simulation , Heart Failure/chemically induced , Heart Failure/drug therapy , Heart Failure/pathology , Myocytes, Cardiac/metabolism , Transforming Growth Factor beta/metabolism , Fibrosis , Transforming Growth Factor beta1/metabolism , Myocardium/metabolism
10.
Phytother Res ; 37(2): 578-591, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36178264

ABSTRACT

Chronic inflammation plays an important role in hypertensive heart failure. Suppressing angiotensin II (Ang II)-induced cardiac inflammation may contribute to the treatment of hypertension-associated heart failure. Sclareol, a natural product initially isolated from the leaves and flowers of Salvia sclarea, possesses antiinflammatory and immune-regulation activity in various systems. However, its effect on Ang II-induced cardiac remodeling remains unknown. In this study, we have explored the potential effects of sclareol on Ang II-induced heart failure. In vivo experiments were conducted in mice with Ang II-pump infusion for 28 days. Sclareol administration at 5 mg·kg-1 ·d-1 significantly reduced the expression of myocardial injury markers. Sclareol also exerts protective effects against Ang II-induced cardiac dysfunction in mice which is associated with alleviated cardiac inflammation and fibrosis. Transcriptome analysis revealed that inhibition of the Ang II-activated mitogen-activated protein kinase (MAPK) pathway contributed to the protective effect of sclareol. Sclareol inhibits Ang II-activated MAPKs pathway to reduce inflammatory response in mouse hearts and cultured cardiomyocytes. Blockage of MAPKs in cardiomyocytes abolished the antiinflammatory effects of sclareol. In conclusion, we show that sclareol protects hearts against Ang II-induced injuries through inhibiting MAPK-mediated inflammation, indicating the potential use of sclareol in the prevention of hypertensive heart failure.


Subject(s)
Heart Failure , Hypertension , Mice , Animals , Mitogen-Activated Protein Kinases/metabolism , Angiotensin II/adverse effects , Ventricular Remodeling/physiology , Heart Failure/chemically induced , Heart Failure/drug therapy , Heart Failure/pathology , Myocytes, Cardiac/metabolism , Hypertension/chemically induced , Hypertension/drug therapy , Fibrosis , Inflammation/drug therapy , Inflammation/pathology , Myocardium/pathology , Mice, Inbred C57BL
11.
Pediatr Blood Cancer ; 70(2): e30059, 2023 02.
Article in English | MEDLINE | ID: mdl-36385736

ABSTRACT

We sought to examine cardiovascular toxicities associated with tyrosine kinase inhibitors in pediatrics. We examined 1624 pediatric adverse events with imatinib, dasatinib, sorafenib, pazopanib, crizotinib, and ruxolitinib reported to the Food and Drug Administration between January 1, 2015, and August 14, 2020. There were 102 cardiovascular event reports. Hypertension was the most commonly reported cardiovascular event and was most frequently associated with sorafenib and pazopanib. The presence of infection increased the reporting odds of cardiovascular events overall and specifically cardiac arrest, heart failure, and hypertension. These data provide early insight into cardiovascular toxicities with tyrosine kinase inhibitor use in pediatrics.


Subject(s)
Antineoplastic Agents , Heart Failure , Hypertension , United States , Humans , Child , Sorafenib/adverse effects , United States Food and Drug Administration , Protein Kinase Inhibitors/adverse effects , Heart Failure/chemically induced , Antineoplastic Agents/adverse effects
12.
J Cell Mol Med ; 26(21): 5414-5425, 2022 11.
Article in English | MEDLINE | ID: mdl-36201630

ABSTRACT

Prevalence of heart failure (HF) continues to rise over time and is a global difficult problem; new drug targets are urgently needed. In recent years, pyroptosis is confirmed to promote cardiac remodelling and HF. Echinacoside (ECH) is a natural phenylethanoid glycoside and is the major active component of traditional Chinese medicine Cistanches Herba, which is reported to possess powerful anti-oxidation and anti-inflammatory effects. In addition, we previously reported that ECH reversed cardiac remodelling and improved heart function, but the effect of ECH on pyroptosis has not been studied. So, we investigated the effects of ECH on cardiomyocyte pyroptosis and the underlying mechanisms. In vivo, we established HF rat models induced by isoproterenol (ISO) and pre-treated with ECH. Indexes of heart function, pyroptotic marker proteins, ROS levels, and the expressions of NOX2, NOX4 and ER stress were measured. In vitro, primary cardiomyocytes of neonatal rats were treated with ISO and ECH; ASC speckles and caspase-1 mediated pyroptosis in cardiomyocytes were detected. Hoechst/PI staining was also used to evaluate pyroptosis. ROS levels, pyroptotic marker proteins, NOX2, NOX4 and ER stress levels were all tested. In vivo, we found that ECH effectively inhibited pyroptosis, down-regulated NOX2 and NOX4, decreased ROS levels, suppressed ER stress and improved heart function. In vitro, ECH reduced cardiomyocyte pyroptosis and suppressed NADPH/ROS/ER stress. We concluded that ECH inhibited cardiomyocyte pyroptosis and improved heart function via suppressing NADPH/ROS/ER stress.


Subject(s)
Heart Failure , Myocytes, Cardiac , Rats , Animals , Myocytes, Cardiac/metabolism , Isoproterenol/pharmacology , Pyroptosis , Reactive Oxygen Species/metabolism , NADP/metabolism , Ventricular Remodeling , Glycosides/pharmacology , Heart Failure/chemically induced , Heart Failure/drug therapy , Heart Failure/metabolism
13.
PLoS One ; 17(9): e0275311, 2022.
Article in English | MEDLINE | ID: mdl-36170343

ABSTRACT

BACKGROUND: Anemia is common in heart failure (HF) patients with chronic kidney disease (CKD) and is associated with worse outcomes. Iron supplementation improves symptoms and is associated with reduced risk of hospitalization for HF in iron-deficiency HF patients. However, iron deficiency is present in <30% of anemic HF patients. Erythropoiesis stimulating agents (ESAs) improve symptoms but are associated with increased risk of thromboembolic events in anemic HF patients with CKD. Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are a new class of agents for the treatment of anemia. These agents work by stabilizing the HIF complex, thereby stimulating endogenous erythropoietin production. We hypothesized that HIF-PH inhibitors may be associated with reduced risk of cardiovascular outcomes compared with ESAs in anemic HF patients with CKD. Accordingly, we aim to perform the meta-analysis of studies on the efficacy and safety of HIF-PH inhibitors compared with ESAs in anemic HF patients with CKD. METHODS: This meta-analysis will include prospective cohort studies and randomized controlled trials on the effect of HIF-PH inhibitors compared with ESAs in anemic HF patients with CKD. Information of studies will be collected from PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov. The primary outcome will be cardiovascular death. The secondary outcomes will be all-cause death, hospitalization for HF, HF symptoms, exercise capacity, health-related quality of life, and hemoglobin levels. DISCUSSION: This meta-analysis will evaluate the effect of HIF-PH inhibitors in anemic HF patients with CKD, providing evidence regarding the use of HIF-PH inhibitors in these patients. SYSTEMATIC REVIEW REGISTRATION: INPLASY202230103.


Subject(s)
Anemia , Erythropoietin , Heart Failure , Hematinics , Prolyl-Hydroxylase Inhibitors , Renal Insufficiency, Chronic , Anemia/complications , Anemia/drug therapy , Heart Failure/chemically induced , Heart Failure/complications , Heart Failure/drug therapy , Hematinics/adverse effects , Hemoglobins , Humans , Hypoxia/complications , Hypoxia-Inducible Factor-Proline Dioxygenases , Iron , Meta-Analysis as Topic , Prospective Studies , Quality of Life , Renal Insufficiency, Chronic/complications , Systematic Reviews as Topic
14.
Medicine (Baltimore) ; 101(30): e29691, 2022 Jul 29.
Article in English | MEDLINE | ID: mdl-35905252

ABSTRACT

BACKGROUND: To assess the benefits and harmful effects of Chinese herbal medicine (CHM) formulations in preventing anthracyclines (ANT)-induced cardiotoxicity. METHOD: The Cochrane Library, Pubmed and EMBASE databases were electronically searched for relevant randomized controlled trials (RCTs) published till December 2021 in English or Chinese-language, in addition to manual searches through the reference lists of the selected papers, and the Chinese Conference Papers Database. Data was extracted by 2 investigators independently. RESULT: Seventeen RCTs reporting 11 different CHMs were included in this meta-analysis. The use of CHM reduced the occurrence of clinical heart failure (RR 0.48, 95% CI 0.39 to 0.60, P < .01) compared to the control group. Data on subclinical heart failure in terms of LVEF values showed that CHM reduced the occurrence of subclinical heart failure (RR 0.47, 95% CI 0.35 to 0.62, P < .01) as well. CONCLUSION: CHM is an effective and safe cardioprotective intervention that can potentially prevent ANT-induced cardiotoxicity. However, due to the insufficient quality of the included trials, our results should be interpreted with cautious.


Subject(s)
Drugs, Chinese Herbal , Heart Failure , Neoplasms , Anthracyclines/adverse effects , Antibiotics, Antineoplastic/therapeutic use , Cardiotoxicity/etiology , Cardiotoxicity/prevention & control , Drugs, Chinese Herbal/therapeutic use , Heart Failure/chemically induced , Heart Failure/drug therapy , Heart Failure/prevention & control , Humans , Neoplasms/drug therapy , Prospective Studies
15.
Phytother Res ; 36(12): 4573-4586, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35906729

ABSTRACT

Qishen granules (QSG), a Chinese herbal formula, has been widely used in the treatment of myocardial ischemic chronic heart failure (CHF) for many years, but its mechanism of action is still unclear. In this study, comprehensive metabolomics was used to investigate the underlying protective mechanisms of QSG in an isoproterenol-induced CHF rat model. A total of 14 biomarkers were identified in serum and 34 biomarkers in urine, which were mainly related to fatty acid metabolism, bile acid metabolism, amino acid metabolism, purine metabolism, vitamin metabolism, and inflammation. Finally, 22 markers were selected for quantitative analysis of serum, urine, and fecal samples to verify the reliability of the results of untargeted metabolomics, and the results were similar to those of untargeted metabolomics. The correlation analysis showed that the targeted quantitative endogenous metabolites and CHF-related indexes were closely related. QSG might alleviate myocardial inflammatory response, oxidative stress, and amino acid metabolism disorder in CHF by regulating the level of endogenous metabolites. This study revealed QSG could regulate potential biomarkers and correlated metabolic pathway, which provided support for the further application of QSG.


Subject(s)
Heart Failure , Metabolomics , Rats , Animals , Isoproterenol/adverse effects , Reproducibility of Results , Heart Failure/chemically induced , Heart Failure/drug therapy , Amino Acids
16.
Exp Cell Res ; 411(2): 113008, 2022 02 15.
Article in English | MEDLINE | ID: mdl-34990617

ABSTRACT

Chronic heart failure (CHF) is one of the most common chronic diseases with increasing incidence and mortality. Liquiritigenin (LQG) is shown to protect mice from cardiotoxicity. However, its underlying mechanism remains unclear. Our study aimed to reveal the role of ARHGAP18 in LQG-mediated cardioprotective effects in CHF. In the current study, CHF cell model and rat model were established by the application of doxorubicin (DOX). The reactive oxygen species (ROS) level and cell apoptosis were determined by flow cytometry. The cardiac function of rats was evaluated by measuring left ventricular systolic pressure, left ventricular end diastolic pressure, and serum level of lactate dehydrogenase and brain natriuretic peptide. The expression of active RhoA was elevated and that of ARHGAP18 was decreased in DOX-induced CHF cell model. ARHGAP18 could reduce DOX-induced RhoA activation, ROS elevation, and cell apoptosis. Meanwhile, the knockdown of ARHGAP18 could promote the activation of RhoA, the level of ROS, and the rate of cell apoptosis, which could be reversed by the application of RhoA inhibitor. LQG promoted the expression of ARHGAP18 and exerted similar effects of ARHGAP18 in CHF cell model. The application of LQG could also reverse the effects mediated by ARHGAP18 knockdown. Moreover, LQG significantly improved cardiac function and ameliorated DOX-induced cardiotoxicity of CHF rats. In conclusion, LQG could alleviate DOX-induced CHF via promoting ARHGAP18 and suppressing RhoA/ROCK1 pathway. LQG was a potential agent for CHF treatment.


Subject(s)
Flavanones/pharmacology , GTPase-Activating Proteins/metabolism , Heart Failure/drug therapy , rho GTP-Binding Proteins/antagonists & inhibitors , rho-Associated Kinases/antagonists & inhibitors , Animals , Apoptosis/drug effects , Cell Line , Chronic Disease , Disease Models, Animal , Down-Regulation , Doxorubicin/toxicity , GTPase-Activating Proteins/antagonists & inhibitors , GTPase-Activating Proteins/genetics , Gene Knockdown Techniques , Glycyrrhiza/chemistry , Heart Failure/chemically induced , Heart Failure/metabolism , Medicine, Chinese Traditional , Plants, Medicinal , Rats , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , rho GTP-Binding Proteins/metabolism , rho-Associated Kinases/metabolism
17.
Pharmacol Res ; 176: 106077, 2022 02.
Article in English | MEDLINE | ID: mdl-35026404

ABSTRACT

Heart failure (HF), the main cause of death in patients with many cardiovascular diseases, has been reported to be closely related to the complicated pathogenesis of autophagy, apoptosis, and inflammation. Notably, Si-Miao-Yong-An decoction (SMYAD) is a traditional Chinese medicine (TCM) used to treat cardiovascular disease; however, the main active components and their relevant mechanisms remain to be discovered. Based on our previous ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) results, we identified angoriside C (AC) and 3,5-dicaffeoylquinic acid (3,5-DiCQA) as the main active components of SMYAD. In vivo results showed that AC and 3,5-DiCQA effectively improved cardiac function, reduced the fibrotic area, and alleviated isoproterenol (ISO)-induced myocarditis in rats. Moreover, AC and 3,5-DiCQA inhibited ISO-induced autophagic cell death by inhibiting the PDE5A/AKT/mTOR/ULK1 pathway and inhibited ISO-induced apoptosis by inhibiting the TLR4/NOX4/BAX pathway. In addition, the autophagy inhibitor 3-MA was shown to reduce ISO-induced apoptosis, indicating that ISO-induced autophagic cell death leads to excess apoptosis. Taken together, the main active components AC and 3,5-DiCQA of SMYAD inhibit the excessive autophagic cell death and apoptosis induced by ISO by inhibiting the PDE5A-AKT and TLR4-NOX4 pathways, thereby reducing myocardial inflammation and improving heart function to alleviate and treat a rat ISO-induced heart failure model and cell heart failure models. More importantly, the main active components of SMYAD will provide new insights into a promising strategy that will promote the discovery of more main active components of SMYAD for therapeutic purposes in the future.


Subject(s)
Chlorogenic Acid/analogs & derivatives , Coumaric Acids/therapeutic use , Drugs, Chinese Herbal , Heart Failure/drug therapy , Trisaccharides/therapeutic use , Animals , Apoptosis/drug effects , Autophagy/drug effects , Cell Line , Cell Survival/drug effects , Chlorogenic Acid/pharmacology , Chlorogenic Acid/therapeutic use , Coumaric Acids/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 5/genetics , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Disease Models, Animal , Heart Failure/chemically induced , Heart Failure/metabolism , Heart Failure/pathology , Isoproterenol , Male , Myoblasts/drug effects , Myocardium/metabolism , Myocardium/pathology , NADPH Oxidase 4/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Rats, Sprague-Dawley , Signal Transduction/drug effects , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Trisaccharides/pharmacology
18.
Biomed Pharmacother ; 146: 112538, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34922111

ABSTRACT

The prognosis of various cardiovascular diseases eventually leads to heart failure (HF). An energy metabolism disorder of cardiomyocytes is important in explaining the molecular basis of HF; this will aid global research regarding treatment options for HF from the perspective of myocardial metabolism. There are many drugs to improve myocardial metabolism for the treatment of HF, including angiotensin receptor blocker-neprilysin inhibitor (ARNi) and sodium glucose cotransporter 2 (SGLT-2) inhibitors. Although Western medicine has made considerable progress in HF therapy, the morbidity and mortality of the disease remain high. Therefore, HF has attracted attention from researchers worldwide. In recent years, the application of traditional Chinese medicine (TCM) in HF treatment has been gradually accepted, and many studies have investigated the mechanism whereby TCM improves myocardial metabolism; the TCMs studied include Danshen yin, Fufang Danshen dripping pill, and Shenmai injection. This enables the clinical application of TCM in the treatment of HF by improving myocardial metabolism. We systematically reviewed the efficacy of TCM for improving myocardial metabolism during HF as well as the pharmacological effects of active TCM ingredients on the cardiovascular system and the potential mechanisms underlying their ability to improve myocardial metabolism. The results indicate that TCM may serve as a complementary and alternative approach for the prevention of HF. However, further rigorously designed randomized controlled trials are warranted to assess the effect of TCM on long-term hard endpoints in patients with cardiovascular disease.


Subject(s)
Cardiovascular Diseases , Drugs, Chinese Herbal , Heart Failure , Salvia miltiorrhiza , Angiotensin Receptor Antagonists/therapeutic use , Cardiovascular Diseases/drug therapy , Drugs, Chinese Herbal/adverse effects , Heart Failure/chemically induced , Heart Failure/drug therapy , Humans , Medicine, Chinese Traditional/methods
19.
J Ethnopharmacol ; 292: 114669, 2022 Jun 28.
Article in English | MEDLINE | ID: mdl-34600079

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Sugemule-3 decoction (SD-3) is a commonly used prescription in Mongolian medicine which composed of the herbs Baidoukou (the fruit of Amomum compactum Sol. ex Maton), Baijusheng (the fruit of Lactuca sativa L.) and Biba (Piper longum L.). SD-3 has remarkable effect on the cardiovascular diseases, but its pharmacological mechanism has not been elucidated. AIM OF THIS STUDY: To evaluate the cardioprotective effects and the potential mechanisms of the ethanol extracts of SD-3 against isoproterenol (ISO)-induced heart failure (HF) in rats. MATERIAL AND METHODS: The ethanol extracts of SD-3 were prepared and analyzed by LC-ESI-MS/MS. One hundred male Wistar rats were randomly divided into five groups: control, ISO (HF) and different doses of SD-3 (0.4, 0.2, 0.1 g/kg/d) groups. HF model rats were established by intraperitoneal injecting of ISO. The left ventricular function was evaluated by echocardiography. Myocardial injury and fibrosis were examined by hematoxylin-eosin (HE) and Masson staining. Western-blot analysis was performed to determine the protein expression of apoptosis and mitochondrial dynamics in all the groups. Moreover, the structural changes in the mitochondria of cardiomyocytes were also observed by transmission electron microscopy. RESULTS: Fifteen compounds were detected in the ethanol extracts of SD-3, include piperine, piperanine, etc. Rats administered with ISO showed a significant decline in the left ventricular function. The cardiac histopathological changes such as local necrosis, interstitial edema, and cardiac fibrosis were also observed in the ISO group. The treatment with SD-3 significantly inhibited these effects of ISO. ISO was found to increase the protein expression of Bax, cleaved-PARP and cleaved-caspase-3, -7 -9, destroy the balance between mitochondrial fusion and fission, and alter the mitochondrial morphology. The ethanol extracts of SD-3 could rebalance mitochondrial fusion and fission, and ameliorates the morphological abnormalities induced by ISO in mitochondria. CONCLUSION: The current study demonstrated that ethanol extracts of SD-3 improved isoprenaline-induced cardiac hypertrophy and fibrosis through inhibiting cardiomyocyte apoptosis and regulating the mitochondrial dynamics.


Subject(s)
Heart Failure , Mitochondrial Dynamics , Animals , Ethanol/chemistry , Fibrosis , Heart Failure/chemically induced , Heart Failure/drug therapy , Heart Failure/prevention & control , Isoproterenol/toxicity , Male , Myocardium/pathology , Rats , Rats, Wistar , Tandem Mass Spectrometry
20.
Biomed Chromatogr ; 36(3): e5294, 2022 Mar.
Article in English | MEDLINE | ID: mdl-34875722

ABSTRACT

The global morbidity and mortality of heart failure has been increasing in recent years. Traditional Chinese medicine (TCM) was increasingly used to treat cardiovascular diseases. Baoyuan decoction (BYD) was a famous classical prescription in China. Modern pharmacological studies showed that it had obvious therapeutic effects on cardiovascular diseases, but its pathological pharmacokinetic studies were unclear. In this research, the absorption of 16 bioactive components in plasma and the excretion of 9 representative components in urine of control rats and isoproterenol (ISO)-induced heart failure rats were studied using the large-volume direct-injection LC-MS method established by our research group. The results indicated that flavonoid constituents exhibited quicker absorption and elimination than saponin constituents after oral administration of BYD. The half-life period of some bioactive compounds in the model group was increased, which contributed to the longer therapeutic effect. The cumulative excretion rate of major flavonoid components of BYD decreased significantly in the ISO-induced heart failure rats.


Subject(s)
Drugs, Chinese Herbal , Heart Failure , Animals , Drugs, Chinese Herbal/pharmacokinetics , Heart Failure/chemically induced , Heart Failure/drug therapy , Medicine, Chinese Traditional , Rats , Rats, Sprague-Dawley
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