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1.
Artigo em Inglês | MEDLINE | ID: mdl-33529089

RESUMO

AIM: Vascular endothelial cell senescence is a leading cause of age-associated diseases and cardiovascular diseases. Interventions and therapies targeting endothelial cell senescence and dysfunction would have important clinical implications. This study was aimed to evaluate the effect of 10 resveratrol analogues, including pterostilbene (Pts) and its derivatives, against endothelial senescence and dysfunction. METHODS AND RESULTS: All the tested compounds at the concentrations from 10-9 M to 10-6 M did not show cytotoxicity in endothelial cells. Among the 10 resveratrol analogues, Pts and Pts nicotinate attenuated the expression of senescence-associated ß-galactosidase, downregulated p21 and p53, and increased the production of NO in both angiotensin II and H2O2-induced endothelial senescence models. In addition, Pts and Pts nicotinate elicited endothelium-dependent relaxations. Pts and Pts nicotinate did not alter Sirtuin 1 (SIRT1) expression but enhanced its activity. Both Pts and Pts nicotinate have high binding activities with SIRT1. Inhibition of SIRT1 by sirtinol reversed the anti-senescent effects of Pts and Pts nicotinate. CONCLUSIONS: This study suggests that the Pts and Pts nicotinate ameliorated vascular endothelial senescence and elicited endothelium-dependent relaxations via activation of SIRT1. These two compounds maybe potential drugs for the treatment of cardiovascular diseases related to endothelial senescence and dysfunction.

2.
Phytomedicine ; 79: 153350, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33002827

RESUMO

BACKGROUND: Vascular endothelial activation is pivotal for the pathological development of various infectious and inflammatory diseases. Therapeutic interventions to prevent endothelial activation are of great clinical significance to achieve anti-inflammatory strategy. Previous studies indicate that the total flavonoids from the endemic herbal medicine Nervilia fordii (Hance) Schltr exerts potent anti-inflammatory effect and protective effect against endotoxin lipopolysaccharide (LPS)-induced acute lung injury, and shows clinical benefit in severe acute respiratory syndromes (SARS). However, the exact effective component of Nervilia fordii and its potential mechanism remain unknown. PURPOSE: The aim of this study was to investigate the effect and mechanism of rhamnocitrin (RH), a flavonoid extracted from Nervilia fordii, on LPS-induced endothelial activation. METHODS: The in vitro endothelial cell activation model was induced by LPS in human umbilical vein endothelial cells (HUVECs). Cell viability was measured to determine the cytotoxicity of RH. RT-PCR, Western blot, fluorescent probe and immunofluorescence were conducted to evaluate the effect and mechanism of RH against endothelial activation. RESULTS: RH was extracted and isolated from Nervilia fordii. RH at the concentration from 10-7 M-10-5 M inhibited the expressions of interlukin-6 (IL-6) and -8 (IL-8), monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) in response to LPS challenge. Mechanistically, RH repressed calcium store-operated Ca2+ entry (SOCE) induced by LPS, which is due to downregulation of stromal interaction molecule-1 (STIM-1) following upregulating microRNA-185 (miR-185). Ultimately, RH abrogated LPS-induced activation of SOCE-mediated calcineurin/NFATc3 (nuclear factor of activated T cells, cytoplasmic 3) signaling pathway. CONCLUSION: The present study identifies RH as a potent inhibitor of endothelial activation. Since vascular endothelial activation is a pivotal cause of excessive cytokine production, leading to cytokine storm and severe pathology in infectious diseases such as SARS and the ongoing COVID-19 pneumonia disease, RH might suggest promising therapeutic potential in the management of cytokine storm in these diseases.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Proteínas Sensoras de Cálcio Intracelular/metabolismo , Quempferóis/farmacologia , Proteínas de Membrana/metabolismo , Fatores de Transcrição NFATC/metabolismo , Proteínas de Neoplasias/metabolismo , Orchidaceae/química , Molécula 1 de Interação Estromal/metabolismo , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Quempferóis/isolamento & purificação , Lipopolissacarídeos/farmacologia , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
3.
Acta Physiol (Oxf) ; : e13555, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32886850

RESUMO

AIM: By activating prostacyclin receptors (IP receptors), prostacyclin (PGI2 ) exerts cardiovascular protective effects such as vasodilation and inhibition of vascular smooth muscle cell (VSMC) proliferation. However, IP receptors are dysfunctional under pathological conditions, and PGI2 produces detrimental effects that are opposite to its physiological protective effects via thromboxane-prostanoid (TP) receptors. This attempted to investigate whether or not IP receptor dysfunction facilitates the shift of PGI2 action. METHODS: The effects of PGI2 and its stable analog iloprost on VSMC phenotypic transformation and proliferation were examined in A10 cells silencing IP receptors, in human aortic VSMCs (HAVSMCs) knocked down IP receptor by CRISPR-Cas9, or in HAVSMCs transfected with a dysfunctional mutation of IP receptor IPR212C . RESULTS: PGI2 /iloprost treatment stimulated cell proliferation, upregulated synthetic proteins and downregulated contractile proteins, suggesting that PGI2 /iloprost promotes VSMC phenotypic transformation in IP-deficient cells. The effect of PGI2 /iloprost was prevented by TP antagonist S18886 or TP knockdown, indicating that the VSMC detrimental effect of PGI2 is dependent on TP receptor. RNA sequencing and Western blotting results showed that RhoA/ROCKs, MEK1/2 and JNK signalling cascades were involved. Moreover, IP deficiency increased the distribution of TP receptors at the cell membrane. CONCLUSION: PGI2 induces VSMC phenotypic transformation when IP receptors are impaired. This is attributed to the activation of TP receptor and its downstream signaling cascades, and to the increased membrane distribution of TP receptors. The VSMC detrimental effect of PGI2 medicated by IP dysfunction and TP activation might probably exacerbate vascular remodelling, accelerating cardiovascular diseases.

4.
Acta Pharmacol Sin ; 41(11): 1377-1386, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32968208

RESUMO

The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and an ongoing severe pandemic. Curative drugs specific for COVID-19 are currently lacking. Chloroquine phosphate and its derivative hydroxychloroquine, which have been used in the treatment and prevention of malaria and autoimmune diseases for decades, were found to inhibit SARS-CoV-2 infection with high potency in vitro and have shown clinical and virologic benefits in COVID-19 patients. Therefore, chloroquine phosphate was first used in the treatment of COVID-19 in China. Later, under a limited emergency-use authorization from the FDA, hydroxychloroquine in combination with azithromycin was used to treat COVID-19 patients in the USA, although the mechanisms of the anti-COVID-19 effects remain unclear. Preliminary outcomes from clinical trials in several countries have generated controversial results. The desperation to control the pandemic overrode the concerns regarding the serious adverse effects of chloroquine derivatives and combination drugs, including lethal arrhythmias and cardiomyopathy. The risks of these treatments have become more complex as a result of findings that COVID-19 is actually a multisystem disease. While respiratory symptoms are the major clinical manifestations, cardiovascular abnormalities, including arrhythmias, myocarditis, heart failure, and ischemic stroke, have been reported in a significant number of COVID-19 patients. Patients with preexisting cardiovascular conditions (hypertension, arrhythmias, etc.) are at increased risk of severe COVID-19 and death. From pharmacological and cardiovascular perspectives, therefore, the treatment of COVID-19 with chloroquine and its derivatives should be systematically evaluated, and patients should be routinely monitored for cardiovascular conditions to prevent lethal adverse events.


Assuntos
Doenças Cardiovasculares/complicações , Cloroquina/análogos & derivados , Cloroquina/uso terapêutico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Antivirais/farmacologia , Cloroquina/farmacologia , Humanos , Pandemias
5.
Pharmacol Res ; 161: 105104, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32739429

RESUMO

BACKGROUND AND PURPOSE: Although histone lysine methylation has been extensively studied for their participation in pathological cardiac hypertrophy, the potential regulatory role of histone arginine methylation remains to be elucidated. The present study focused on H4R3 symmetric di-methylation (H4R3me2s) induced by protein arginine methyltransferase 5 (Prmt5), and explored its epigenetic regulation and underlying mechanisms in cardiomyocyte hypertrophy. METHODS AND RESULTS: 1. The expressions of Prmt5 and H4R3me2s were suppressed in cardiac hypertrophy models in vivo and in vitro; 2. Prmt5 silencing or its inhibitor EPZ, or knockdown of cooperator of Prmt5 (Copr5) to disrupt H4R3me2s, facilitated cardiomyocyte hypertrophy, whereas overexpression of wild type Prmt5 rather than the inactive mutant protected cardiomyocytes against hypertrophy; 3. ChIP-sequence analysis identified Filip1L as a target gene of Prmt5-induced H4R3me2s; 4. Knockdown or inhibition of Prmt5 impaired Filip1L transcription and subsequently prevented ß-catenin degradation, thus augmenting cardiomyocyte hypertrophy. CONCLUSIONS: The present study reveals that Prmt5-induced H4R3me2s ameliorates cardiomyocyte hypertrophy by transcriptional upregulation of Filip1L and subsequent enhancement of ß-catenin degradation. Deficiency of Prmt5 and the resulting suppression of H4R3me2s might facilitate the development of pathological cardiac hypertrophy. Prmt5 might serve as a key epigenetic regulator in pathological cardiac hypertrophy.

7.
J Med Chem ; 62(7): 3707-3721, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30888810

RESUMO

Pulmonary arterial hypertension (PAH) causes pathological increase in pulmonary vascular resistance, leading to right-heart failure and eventual death. Previously, phosphodiesterase-10 (PDE10) was reported to be a promising target for PAH based on the studies with a nonselective PDE inhibitor papaverine, but little progress has been made to confirm the practical application of PDE10 inhibitors. To validate whether PAH is ameliorated by PDE10 inhibition rather than other PDE isoforms, here we report an integrated strategy to discover highly selective PDE10 inhibitors as chemical probes. Structural optimization resulted in a PDE10 inhibitor 2b with subnanomolar affinity and good selectivity of >45 000-fold against other PDEs. The cocrystal structure of the PDE10-2b complex revealed an important H-bond interaction between 2b and Tyr693. Finally, compound 2b significantly decreased the arterial pressure in PAH rats and thus validated the potential of PDE10 as a novel anti-PAH target. These findings suggest that PDE10 inhibition may be a viable treatment option for PAH.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Animais , Cristalografia por Raios X , Humanos , Masculino , Simulação de Dinâmica Molecular , Músculo Liso/efeitos dos fármacos , Músculo Liso/enzimologia , Diester Fosfórico Hidrolases/química , Fator de Crescimento Derivado de Plaquetas/farmacologia , Ligação Proteica , Conformação Proteica , Ratos
8.
Br J Pharmacol ; 176(3): 416-435, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30414383

RESUMO

BACKGROUND AND PURPOSE: Activation of PKC-ζ is closely linked to the pathogenesis of cardiac hypertrophy. PKC-ζ can be activated by certain lipid metabolites such as phosphatidylinositol (3,4,5)-trisphosphate and ceramide. However, its endogenous negative regulators are not well defined. Here, the role of the sirtuin1-PKC-ζ signalling axis and the underlying molecular mechanisms were investigated in cardiac hypertrophy. EXPERIMENTAL APPROACH: Cellular hypertrophy in cultures of cardiac myocytes, from neonatal Sprague-Dawley rats, was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Interaction between sirtuin1 and PKC-ζ was investigated by co-immunoprecipitation and confocal immunofluorescence microscopy. Sirtuin1 activation was enhanced by resveratrol treatment or Ad-sirtuin1 transfection. A model of cardiac hypertrophy in Sprague-Dawley rats was established by abdominal aortic constriction surgery or induced by isoprenaline in vivo. KEY RESULTS: Overexpression of PKC-ζ led to cardiac hypertrophy and increased activity of NF-κB, ERK1/2 and ERK5, which was ameliorated by sirtuin1 overexpression. Enhancement of sirtuin1 activity suppressed acetylation of PKC-ζ, hindered its binding to phosphoinositide-dependent kinase 1 and inhibited PKC-ζ phosphorylation in cardiac hypertrophy. Consequently, the downstream pathways of PKC-ζ' were suppressed in cardiac hypertrophy. This regulation loop suggests a new role for sirtuin1 in mediation of cardiac hypertrophy. CONCLUSIONS AND IMPLICATIONS: Sirtuin1 is an endogenous negative regulator for PKC-ζ and mediates its activity via regulating the acetylation and phosphorylation in the pathogenesis of cardiac hypertrophy. Targeting the sirtuin1-PKC-ζ signalling axis may suggest a novel therapeutic approach against cardiac hypertrophy.


Assuntos
Cardiomegalia/metabolismo , Proteína Quinase C/metabolismo , Sirtuína 1/metabolismo , Acetilação , Animais , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley
9.
Acta Pharmacol Sin ; 40(5): 589-598, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30030529

RESUMO

High-mobility group box 1 (HMGB1) exhibits various functions according to its subcellular location, which is finely conditioned by diverse post-translational modifications, such as acetylation. The nuclear HMGB1 may prevent from cardiac hypertrophy, whereas its exogenous protein is proven to induce hypertrophic response. This present study sought to investigate the regulatory relationships between poly(ADP-ribose) polymerase 1 (PARP1) and HMGB1 in the process of pathological myocardial hypertrophy. Primary-cultured neonatal rat cardiomyocytes (NRCMs) were respectively incubated with three cardiac hypertrophic stimulants, including angiotensin II (Ang II), phenylephrine (PE), and isoproterenol (ISO), and cell surface area and the mRNA expression of hypertrophic biomarkers were measured. the catalytic activity of PARP1 was remarkably enhanced, meanwhile HMGB1 excluded from the nucleus. PARP1 overexpression by infecting with adenovirus PARP1 (Ad-PARP1) promoted the nuclear export of HMGB1, facilitated its secretion outside the cell, aggravated cardiomyocyte hypertrophy, which could be alleviated by HMGB1 overexpression. PE treatment led to the similar results, while that effect was widely depressed by PARP1 silencing or its specific inhibitor AG14361. Moreover, SD rats were intraperitoneally injected with 3-aminobenzamide (3AB, 20 mg/kg every day, a well-established PARP1 inhibitor) 7 days after abdominal aortic constriction (AAC) surgery for 6 weeks, echocardiography and morphometry of the hearts were measured. Pre-treatment of 3AB relieved AAC-caused the translocation of nuclear HMGB1 protein, cardiac hypertrophy, and heart dysfunction. Our research offers a novel evidence that PARP1 combines with HMGB1 and accelerates its translocation from nucleus to cytoplasm, and the course finally causes cardiac hypertrophy.


Assuntos
Cardiomegalia/etiologia , Núcleo Celular/metabolismo , Proteína HMGB1/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Angiotensina II/farmacologia , Animais , Isoproterenol/farmacologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Fenilefrina/farmacologia , Ratos Sprague-Dawley
10.
Aging (Albany NY) ; 10(7): 1722-1744, 2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-30048241

RESUMO

AIM: Premature senescence of vascular endothelial cells is a leading cause of various cardiovascular diseases. Therapies targeting endothelial senescence would have important clinical implications. The present study was aimed to evaluate the potential of heme oxygenase-1 (HO-1) as a therapeutic target for endothelial senescence. METHODS AND RESULTS: Upregulation of HO-1 by Hemin or adenovirus infection reversed H2O2-induced senescence in human umbilical vein endothelial cells (HUVECs); whereas depletion of HO-1 by siRNA or HO-1 inhibitor protoporphyrin IX zinc (II) (ZnPP) triggered HUVEC senescence. Mechanistically, overexpression of HO-1 enhanced the interaction between HO-1 and endothelial nitric oxide synthase (eNOS), and promoted the interaction between eNOS and its upstream kinase Akt, thus resulting in an enhancement of eNOS phosphorylation at Ser1177 and a subsequent increase of nitric oxide (NO) production. Moreover, HO-1 induction prevented the decrease of eNOS dimer/monomer ratio stimulated by H2O2 via its antioxidant properties. Contrarily, HO-1 silencing impaired eNOS phosphorylation and accelerated eNOS uncoupling. In vivo, Hemin treatment alleviated senescence of endothelial cells of the aorta from spontaneously hypertensive rats, through upregulating eNOS phosphorylation at Ser1177. CONCLUSIONS: HO-1 ameliorated endothelial senescence through enhancing eNOS activation and defending eNOS uncoupling, suggesting that HO-1 is a potential target for treating endothelial senescence.


Assuntos
Senescência Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hemina/farmacologia , Peróxido de Hidrogênio/toxicidade , Óxido Nítrico Sintase Tipo III/metabolismo , Adenoviridae/fisiologia , Animais , Células Cultivadas , Senescência Celular/fisiologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1 , Humanos , Óxido Nítrico Sintase Tipo III/genética , Estresse Oxidativo , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Regulação para Cima
12.
Acta Pharmacol Sin ; 39(12): 1837-1846, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29991711

RESUMO

Vascular endothelial cell senescence is a leading cause of age-associated and vascular diseases. Mammalian target of rapamycin complex 2 (mTORC2) is a conserved serine/threonine (Ser/Thr) protein kinase that plays an important regulatory role in various cellular processes. However, its impact on endothelial senescence remains controversial. In this study we investigated the role and molecular mechanisms of mTORC2 in endothelial senescence. A replicative senescence model and H2O2-induced premature senescence model were established in primary cultured human umbilical vein endothelial cells (HUVECs). In these senescence models, the formation and activation of mTORC2 were significantly increased, evidenced by the increases in binding of Rictor (the essential component of mTORC2) to mTOR, phosphorylation of mTOR at Ser2481 and phosphorylation of Akt (the effector of mTORC2) at Ser473. Knockdown of Rictor or treatment with the Akt inhibitor MK-2206 attenuated senescence-associated ß-galactosidase (ß-gal) staining and expression of p53 and p21 proteins in the senescent endothelial cells, suggesting that mTORC2/Akt facilitates endothelial senescence. The effect of mTORC2/Akt on endothelial senescence was due to suppression of nuclear factor erythroid 2-related factor 2 (Nrf2) at the transcriptional level, since knockdown of Rictor reversed the reduction of Nrf2 mRNA expression in endothelial senescence. Furthermore, mTORC2 suppressed the expression of Nrf2 via the Akt/GSK-3ß/C/EBPα signaling pathway. These results suggest that the mTORC2/Akt/GSK-3ß/C/EBPα/Nrf2 signaling pathway is involved in both replicative and inducible endothelial senescence. The deleterious role of mTORC2 in endothelial cell senescence suggests therapeutic strategies (targeting mTORC2) for aging-associated diseases and vascular diseases.


Assuntos
Senescência Celular/fisiologia , Células Endoteliais/fisiologia , Alvo Mecanístico do Complexo 2 de Rapamicina/fisiologia , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia
13.
Comput Biol Chem ; 74: 339-346, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29723807

RESUMO

Polycomb CBX proteins regulate gene expression by targeting Polycomb repressive complex 1 (PRC1) to sites of H3K27me3 via their chromodomains, which plays a key role in the development of numerous cancers. UNC3866, is a recently reported peptide-based inhibitor of the methyllysine (Kme) reading function of CBX chromodomains (CBX2, 4 and 6-8). The previous experiments showed that UNC3866 bound the chromodomains of CBX7 strongly, with ∼20-fold selectivity over other CBX chromodomains. However, the potential mechanism of UNC3866 preferentially binding to CBX7 is still unknown. In this study, we performed two pairs of microsecond molecular dynamic simulations (CBX2 (-UNC3866)) and (CBX7 (-UNC3866)) to study the inhibition and isoform-selective mechanism of UNC3866 to CBX7. The conformational analysis of apo- and holo- CBX2 and CBX7 indicated that the aromatic cage of CBX7 protein was more prone to be induced by UNC3866 relative to CBX2 protein. The results of predicted binding free energy suggested the binding affinity of UNC3866 with CBX7 was stronger than that with CBX2, because of the lower binding free energy of the former. Furthermore, the energetic origin of UNC3866 selective for CBX7 protein mainly came from the higher van der Waals contributions. The binding mode analysis showed that Asn47 of CBX2 formed a hydrogen bond with the OH group of C-terminal cap of UNC3866, inducing the conformational changes of diethyllysine of UNC3866 that is obviously different from that in CBX7. Additionally, His39 in CBX2 chromodomain interrupted the structured aromatic cage, partly explaining the reason for UNC3866 preferring for binding to CBX7. The proposal of this selective mechanism could be helpful for the rational design of novel selective inhibitors of the Polycomb CBX protein.


Assuntos
Simulação de Dinâmica Molecular , Oligopeptídeos/farmacologia , Complexo Repressor Polycomb 1/antagonistas & inibidores , Análise por Conglomerados , Humanos , Conformação Molecular , Oligopeptídeos/química , Complexo Repressor Polycomb 1/metabolismo , Relação Estrutura-Atividade , Termodinâmica
14.
Acta Pharmacol Sin ; 39(5): 802-824, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29698387

RESUMO

Salvia miltiorrhiza Burge (Danshen) is an eminent medicinal herb that possesses broad cardiovascular and cerebrovascular protective actions and has been used in Asian countries for many centuries. Accumulating evidence suggests that Danshen and its components prevent vascular diseases, in particular, atherosclerosis and cardiac diseases, including myocardial infarction, myocardial ischemia/reperfusion injury, arrhythmia, cardiac hypertrophy and cardiac fibrosis. The published literature indicates that lipophilic constituents (tanshinone I, tanshinone IIa, tanshinone IIb, cryptotanshinone, dihydrotanshinone, etc) as well as hydrophilic constituents (danshensu, salvianolic acid A and B, protocatechuic aldehyde, etc) contribute to the cardiovascular protective actions of Danshen, suggesting a potential synergism among these constituents. Herein, we provide a systematic up-to-date review on the cardiovascular actions and therapeutic potential of major pharmacologically active constituents of Danshen. These bioactive compounds will serve as excellent drug candidates in small-molecule cardiovascular drug discovery. This article also provides a scientific rationale for understanding the traditional use of Danshen in cardiovascular therapeutics.


Assuntos
Cardiotônicos/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Animais , Doenças Cardiovasculares/fisiopatologia , Sinergismo Farmacológico , Células Endoteliais/efeitos dos fármacos , Fibrinolíticos/uso terapêutico , Humanos , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Salvia miltiorrhiza
15.
Mol Cell Endocrinol ; 474: 137-150, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-29501586

RESUMO

The activation of signal transducer and activator of transcription 3 (STAT3) positively regulates myocardial hypertrophy, and its transcriptional activity is finely conditioned by diverse extracellular growth factors and cytokines. Here, we introduce novel evidence that poly(ADP-ribose) polymerase 1 (PARP1) interacts with STAT3 and promotes its activation in cardiomyocytes and rat heart tissues. PARP1 activity and phosphorylated STAT3 were augmented by hypertrophic stimuli both in vitro and in vivo. Infection of PARP1 adenovirus induced cardiomyocyte hypertrophy, which could be prevented by STAT3 knockdown or inhibition. Additionally, PARP1 enhanced STAT3 phosphorylation level, nuclear accumulation and transcriptional activity. Mechanistically, PARP1 interacts with STAT3 and retains active phosphorylated-STAT3 in nucleus. In conclusion, our findings provide the first evidence that PARP1 exacerbates cardiac hypertrophy by stabilizing active phosphorylated-STAT3, which suggests that multi-target therapeutic strategies counteracting PARP1 activity and STAT3 activation would be potential for treating cardiovascular diseases.


Assuntos
Cardiomegalia/metabolismo , Cardiomegalia/patologia , Núcleo Celular/metabolismo , Miocárdio/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Cardiomegalia/genética , Núcleo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Janus Quinase 2/metabolismo , Masculino , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fenilefrina/farmacologia , Fosforilação/efeitos dos fármacos , Pressão , Ligação Proteica/efeitos dos fármacos , Ratos Sprague-Dawley , Transcrição Genética/efeitos dos fármacos
16.
Front Pharmacol ; 9: 1519, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30670969

RESUMO

NFATc4, a member from the Nuclear Factor of Activated T cells (NFATs) transcription factor family, plays a pivotal role in the development of cardiac hypertrophy. NFATc4 is dephosphorylated by calcineurin and translocated from the cytoplasm to the nucleus to regulate the expression of hypertrophic genes, like brain natriuretic polypeptide (BNP). The present study identified SIRT6, an important subtype of NAD+ dependent class III histone deacetylase, to be a negative regulator of NFATc4 in cardiomyocyte hypertrophy. In phenylephrine (PE)-induced hypertrophic cardiomyocyte model, overexpression of SIRT6 by adenovirus infection or by plasmid transfection repressed the protein and mRNA expressions of NFATc4, elevated its phosphorylation level, prevented its nuclear accumulation, subsequently suppressed its transcriptional activity and downregulated its target gene BNP. By contrast, mutant of SIRT6 without deacetylase activity (H133Y) did not demonstrate these effects, suggesting that the inhibitory effect of SIRT6 on NFATc4 was dependent on its deacetylase activity. Moreover, the effect of SIRT6 overexpression on repressing BNP expression was reversed by NFATc4 replenishment, whereas the effect of SIRT6 deficiency on upregulating BNP was recovered by NFATc4 silencing. Mechanistically, interactions between SIRT6 and NFATc4 might possibly facilitate the deacetylation of NFATc4 by SIRT6, thereby preventing the activation of NFATc4. In conclusion, the present study reveals that SIRT6 suppresses the expression and activation of NFATc4. These findings provide more evidences of the anti-hypertrophic effect of SIRT6 and suggest SIRT6 as a potential therapeutic target for cardiac hypertrophy.

17.
Mol Cell Endocrinol ; 460: 1-13, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-28579116

RESUMO

Silent mating type information regulation 2 homolog 3 (SIRT3) is a major protective mediator that ameliorates oxidative stress and mitochondrial dysfunction, which are associated with the pathogenesis of epithelial-mesenchymal transition (EMT). The present study was aimed to investigate the potential role of SIRT3 in renal tubular EMT both in vitro and in vivo. Firstly, we showed that the expression of SIRT3 was repressed in angiotensin II-induced EMT. SIRT3 deficiency triggered EMT response, while over-expression of SIRT3 attenuated EMT response. In addition, over-expression of SIRT3 repressed AngⅡ-induced excessive production of mitochondrial superoxide, as well as mitochondrial dysfunction evidenced by the maintenance of mitochondrial number and morphology, and the stabilization of mitochondrial membrane potential. In conclusion, these findings identify a protective role of SIRT3 against angiotensin II-induced EMT in the kidney, and suggest SIRT3 upregulation is a potential therapeutic strategy for the treatment of renal tubulointerstitial fibrosis.


Assuntos
Transição Epitelial-Mesenquimal , Túbulos Renais/patologia , Mitocôndrias/patologia , Estresse Oxidativo , Sirtuína 3/metabolismo , Angiotensina II , Animais , Pressão Sanguínea , Linhagem Celular , Citoproteção , Regulação para Baixo , Túbulos Renais/ultraestrutura , Potencial da Membrana Mitocondrial , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Ratos , Sirtuína 3/deficiência , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Sístole
18.
Chemosphere ; 191: 458-466, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29055267

RESUMO

The isolation of fulvic acid (FA) fractions with relatively homogeneity is a key to reveal the binding mechanisms between FA and heavy metals. In this work, nine FA fractions were obtained using sequential alkali extraction procedure and nature differences of the extracted FA fractions were considered as explanatory factors for binding characteristics of Cu2+. The results indicate that the contents of carboxyl and phenolic groups decrease with increasing extractions along with an opposite trend for the content of nitrogen-containing groups. The fitted results of ligand binding and bi-Langmuir models indicate that the binding sites for Cu2+ were mainly provided by carboxyl and phenolic groups, which explained the higher sorption capacity and binding affinity of earlier extracted FAs due to its higher contents of carboxyl and phenolic groups. Furthermore, the systemic characterization of FA fractions before and after adsorption indicate the nitrogen-containing groups were gradually showing their contribution in binding Cu2+ with increasing extractions. This work is very helpful to insight the environmental effects of natural organic matter and the behavior of heavy metals in natural environment.


Assuntos
Benzopiranos/química , Cobre/química , Monitoramento Ambiental , Adsorção , Benzopiranos/análise , Fracionamento Químico , Metais Pesados/química , Nitrogênio/química
19.
Acta Pharmacol Sin ; 38(9): 1257-1268, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28649129

RESUMO

Phosphodiesterase-9A (PDE9A) expression is upregulated during cardiac hypertrophy and heart failure. Accumulating evidence suggests that PDE9A might be a promising therapeutic target for heart diseases. The present study sought to investigate the effects and underlying mechanisms of C33(S), a novel selective PDE9A inhibitor, on cardiac hypertrophy in vitro and in vivo. Treatment of neonatal rat cardiomyocytes (NRCMs) with PE (100 µmol/L) or ISO (1 µmol/L) induced cardiac hypertrophy characterized by significantly increased cell surface areas and increased expression of fetal genes (ANF and BNP). Furthermore, PE or ISO significantly increased the expression of PDE9A in the cells; whereas knockdown of PDE9A significantly alleviated PE-induced hypertrophic responses. Moreover, pretreatment with PDE9A inhibitor C33(S) (50 and 500 nmol/L) or PF-7943 (2 µmol/L) also alleviated the cardiac hypertrophic responses in PE-treated NRCMs. Abdominal aortic constriction (AAC)-induced cardiac hypertrophy and ISO-induced heart failure were established in SD rats. In ISO-treated rats, oral administration of C33(S) (9, 3, and 1 mg·kg-1·d-1, for 3 consecutive weeks) significantly increased fractional shortening (43.55%±3.98%, 54.79%±1.95%, 43.98%±7.96% vs 32.18%±6.28%), ejection fraction (72.97%±4.64%, 84.29%±1.56%, 73.41%±9.37% vs 49.17%±4.20%) and cardiac output (60.01±9.11, 69.40±11.63, 58.08±8.47 mL/min vs 48.97±2.11 mL/min) but decreased the left ventricular internal diameter, suggesting that the transition to heart failure was postponed by C33(S). We further revealed that C33(S) significantly elevated intracellular cGMP levels, phosphorylation of phospholamban (PLB) and expression of SERCA2a in PE-treated NRCMs in vitro and in ISO-induced heart failure model in vivo. Our results demonstrate that C33(S) effectively protects against cardiac hypertrophy and postpones the transition to heart failure, suggesting that it is a promising agent in the treatment of cardiac diseases.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Cardiomegalia/tratamento farmacológico , GMP Cíclico/metabolismo , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Animais , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Pirazóis/administração & dosagem , Pirazóis/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
20.
Acta Pharmacol Sin ; 38(5): 638-650, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28239158

RESUMO

We previously identified AG-690/11026014 (6014) as a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor that effectively prevented angiotensin II (Ang II)-induced cardiomyocyte hypertrophy. In the present study, we reported a new synthesis route for 6014, and investigated its protective effects on Ang II-induced cardiac remodeling and cardiac dysfunction and the underlying mechanisms in mice. We designed a new synthesis route to obtain a sufficient quantity of 6014 for this in vivo study. C57BL/6J mice were infused with Ang II and treated with 6014 (10, 30, 90 mg·kg-1·d-1, ig) for 4 weeks. Then two-dimensional echocardiography was performed to assess the cardiac function and structure. Histological changes of the hearts were examined with HE staining and Masson's trichrome staining. The protein expression was evaluated by Western blot, immunohistochemistry and immunofluorescence assays. The activities of sirtuin-1 (SIRT-1) and the content of NAD+ were detected with the corresponding test kits. Treatment with 6014 dose-dependently improved cardiac function, including LVEF, CO and SV and reversed the changes of cardiac structure in Ang II-infused mice: it significantly ameliorated Ang II-induced cardiac hypertrophy evidenced by attenuating the enlargement of cardiomyocytes, decreased HW/BW and LVW/BW, and decreased expression of hypertrophic markers ANF, BNP and ß-MHC; it also prevented Ang II-induced cardiac fibrosis, as implied by the decrease in excess accumulation of extracellular matrix (ECM) components collagen I, collagen III and FN. Further studies revealed that treatment with 6014 did not affect the expression levels of PARP-1, but dose-dependently inhibited the activity of PARP-1 and subsequently restored the activity of SIRT-1 in heart tissues due to the decreased consumption of NAD+ and attenuated Poly-ADP-ribosylation (PARylation) of SIRT-1. In conclusion, the novel PARP-1 inhibitor 6014 effectively protects mice against AngII-induced cardiac remodeling and improves cardiac function. Thus, 6014 might be a potential therapeutic agent for heart diseases..


Assuntos
Cardiomegalia/terapia , Cardiotônicos/uso terapêutico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Tioglicolatos/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Xantinas/uso terapêutico , Angiotensina II/farmacologia , Animais , Cardiomegalia/induzido quimicamente , Cardiotônicos/síntese química , Fibrose/induzido quimicamente , Fibrose/terapia , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Sirtuína 1/metabolismo , Tioglicolatos/síntese química , Xantinas/síntese química
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