Circulating miRNAs as Potential Biomarkers Associated with Cardiac Remodeling and Fibrosis in Chagas Disease Cardiomyopathy

Chagas disease (CD) affects approximately 6–7 million people worldwide, from which 30% develop chronic Chagas cardiomyopathy (CCC), usually after being asymptomatic for years. Currently available diagnostic methods are capable of adequately identifying infected patients, but do not provide information regarding the individual risk of developing the most severe form of the disease. The identification of biomarkers that predict the progression from asymptomatic or indeterminate form to CCC, may guide early implementation of pharmacological therapy. Here, six circulating microRNAs (miR-19a-3p, miR-21-5p, miR-29b-3p, miR-30a-5p, miR-199b-5p and miR-208a-3p) were evaluated and compared among patients with CCC (n = 28), CD indeterminate form (n = 10) and healthy controls (n = 10). MiR-19a-3p, miR-21-5p, and miR-29b-3p were differentially expressed in CCC patients when compared to indeterminate form, showing a positive correlation with cardiac dysfunction, functional class, and fibrosis, and a negative correlation with ejection fraction and left ventricular strain. Cardiac tissue analysis confirmed increased expression of microRNAs in CCC patients. In vitro studies using human cells indicated the involvement of these microRNAs in the processes of cardiac hypertrophy and fibrosis. Our study suggests that miRNAs are involved in the process of cardiac fibrosis and remodeling presented in CD and indicate a group of miRNAs as potential biomarkers of disease progression in CCC.

Download Full-text

T-Cell Immunophenotyping and Cytokine Production Analysis in Patients with Chagas Disease 4 Years after Benznidazole Treatment

Infection and Immunity ◽

10.1128/iai.00103-19 ◽

2019 ◽

Vol 87 (8) ◽

Cited By ~ 2

Author(s):

Mauricio Llaguno ◽

Marcos Vinicius da Silva ◽

Lara Rocha Batista ◽

Djalma Alexandre Alves da Silva ◽

Rodrigo Cunha de Sousa ◽

...

Keyword(s):

Chagas Disease ◽

Chronic Phase ◽

Interleukin 10 ◽

T Helper ◽

T Helper 1 ◽

Cardiac Damage ◽

Disease Treatment ◽

Indeterminate Form ◽

Ifn Γ

ABSTRACT The major problem with Chagas disease is evolution of the chronic indeterminate form to a progressive cardiac disease. Treatment diminishes parasitemia but not clinical progression, and the immunological features involved are unclear. Here, we studied the clinical course and the immune response in patients with chronic-phase Chagas disease at 48 months after benznidazole treatment. Progression to the cardiac form of Chagas disease or its aggravation was associated with higher in vitro antigen-specific production of interferon gamma (IFN-γ) in patients with cardiac Chagas disease than in patients with the indeterminate form. Predominance of IFN-γ production over interleukin-10 (IL-10) production in antigen-specific cultures was associated with cardiac involvement. Significantly higher numbers of antigen-specific T helper 1 cells (T-Bet+ IFN-γ+) and a significantly higher IFN-γ+/IL-10+ ratio were observed in patients with cardiac Chagas disease than in patients with the indeterminate form. Cardiac damage was associated with higher numbers of T helper cells than cytotoxic T lymphocytes producing IFN-γ. Patients with cardiac Chagas disease had predominant CD25− and CD25low T regulatory (Treg) subpopulations, whereas patients with the indeterminate form manifested a higher relative mean percentage of CD25high Treg subpopulations. These findings suggest that at 48 months after benznidazole treatment, the disease can worsen or progress to the cardiac form. The progression may be related to increased IFN-γ production (mostly from CD4+ T cells) relative to IL-10 production and increased Treg percentages. Patients with the indeterminate form of Chagas disease show a more balanced ratio of proinflammatory and anti-inflammatory cytokines.

Download Full-text

Early impairment of myocardial deformation assessed by regional speckle-tracking echocardiography in the indeterminate form of Chagas disease without fibrosis detected by cardiac magnetic resonance

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0008795 ◽

2020 ◽

Vol 14 (11) ◽

pp. e0008795

Author(s):

Minna Moreira Dias Romano ◽

Henrique Turin Moreira ◽

José Antônio Marin-Neto ◽

Priscila Elias Baccelli ◽

Fawaz Alenezi ◽

...

Keyword(s):

Cardiac Magnetic Resonance ◽

Magnetic Resonance ◽

Myocardial Fibrosis ◽

Chagas Disease ◽

Speckle Tracking ◽

Longitudinal Strain ◽

Speckle Tracking Echocardiography ◽

Global Longitudinal Strain ◽

Left Ventricular ◽

Indeterminate Form

Chagas disease (CD) will account for 200,000 cardiovascular deaths worldwide over the next 5 years. Early detection of chronic Chagas cardiomyopathy (CCC) is a challenge. We aimed to test if speckle-tracking echocardiography (STE) can detect incipient myocardial damage in CD. METHODS: Among 325 individuals with positive serological tests, 25 (age 55±12yrs) were selected to compose the group with indeterminate form of Chagas disease (IFCD), based on stringent criteria of being asymptomatic and with normal EKG/X-ray studies. This group was compared with a group of 20 patients with CCC (55±11yrs) and a group of 20 non-infected matched control (NC) subjects (48±10yrs). CD patients and NC were submitted to STE and CD patients were submitted to cardiac magnetic resonance (CMR) with late gadolinium administration to detect cardiac fibrosis by the late enhancement technique. Global longitudinal strain (GLS), circumferential (GCS) and radial strain (GRS) were defined as the average of segments measured from three apical view (GLS) and short axis views (GRS and GCS). Regional left ventricular (LV) longitudinal strain (Reg LS) was measured from each of the 17 segments. Twist was measured as systolic peak difference between basal and apical rotation and indexed to LV length to express torsion. RESULTS: STE global indices (GLS, GCS, twist and torsion) were reduced in CCC vs NC (GLS: -14±6.3% vs -19.3±1.6%, p = 0.001; GCS: -13.6±5.2% vs -17.3 ±2.8%; p = 0.008; twist: 8±7° vs 14±7°, p = 0.01 and torsion: 0.96±1°/cm vs 1.9±1°/cm, p = 0.005), but showed no differences in IFCD vs NC. RegLS was reduced in IFCD vs NC in four LV segments: basal-inferior (-16.3±3.3% vs -18.6±2.2%, p = 0.013), basal inferoseptal (-13.1±3.4 vs -15.2±2.7, p = 0.019), mid-inferoseptal (-17.7±3.2 vs -19.4±2, p = 0.032) and mid-inferolateral (-15.2±3.5 vs -17.8±2.8, p = 0.014). These abnormalities in RegLS occurred in the absence of myocardial fibrosis detectable with CMR in nearly 92% of subjects with IFCD, while myocardial fibrosis was present in 65% with CCC. CONCLUSION: RegLS detects early regional impairment of myocardial strain that is independent from fibrosis in IFCD subjects.

Download Full-text

Low‐intensity Pulsed Ultrasound Ameliorates Angiotension Ii-induced Cardiac Fibrosisbyalleviating Inflammation via a Caveolin-1-dependent Pathway

10.21203/rs.3.rs-37027/v1 ◽

2020 ◽

Author(s):

Kun Zhao ◽

Jing Zhang ◽

Tianhua Xu ◽

Chuanxi Yang ◽

Liqing Weng ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Cardiac Fibrosis ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Left Ventricular ◽

Pulsed Ultrasound ◽

Caveolin 1 ◽

Low Intensity Pulsed Ultrasound

Abstract Background: Cardiac hypertrophy and fibrosis are major pathological manifestations observed in left ventricular remodeling induced by Angiotensin II (AngII). Concerning the fact that low‐intensity pulsed ultrasound (LIPUS) has been reported to improve cardiac dysfunction and myocardial fibrosis in myocardial infarction (MI) through mechanotransductionanditsdownstream pathways, we aimed to investigate whether LIPUS could also exert a protective effect on ameliorating AngII-induced cardiac hypertrophy and fibrosis andand if so, to further elucidate the underlying molecular mechanisms.Methods: In our study, we used AngII to mimic the animal and cell culture models of cardiac hypertrophy and fibrosis, where LIPUS irradiation (0.5MHz, 77.20mW/cm2) was applied for 20 minutes every 2 days from 1 week before surgery to 4 weeks after surgery in vivo, and every 6 hours for a total of 2 times in vitro. Following that, the levels of cardiac hypertrophy and fibrosis were evaluated by echocardiographic, histopathological, and molecular biological methods. Results: Our results showed that LIPUS irradiation could ameliorate left ventricular remodeling in vivo and cardiac fibrosis in vitro by reducing AngII-inducedrelease of inflammatory cytokines, while the protective effects were limited on cardiac hypertrophy in vitro. Given that LIPUS irradiation increased the expression of caveolin-1 related to mechanical stimulation, we inhibited caveolin-1 activity with pyrazolopyrimidine 2 (pp2) in vitro, by which LIPUS-induced downregulation of inflammation was reversed and the anti-fibrosis effects of LIPUS irradiation were absent. Conclusions: Taken together, these results indicate that LIPUS irradiation could ameliorate AngII-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway, providing new insights for the development of novel therapeuticapparatus in clinical practice.

Download Full-text

FC 064A RENAL-CARDIO INFLAMMATORY AXIS MEDIATES CARDIAC DYSFUNCTION IN CKD VIA IL-33-ST2: A NOVEL MECHANISM

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab136.003 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Alejandro Chade ◽

Michael Hall ◽

Deandra Fortenberry ◽

Drew Bossier ◽

Gene Bidwell

Keyword(s):

Cardiac Fibrosis ◽

Left Ventricular ◽

Cellular Damage ◽

Heart Weight ◽

Swine Model ◽

Renal Inflammation ◽

Cardiac Abnormalities ◽

Tnf Α

Abstract Background and Aims We developed a swine model of chronic kidney disease (CKD) that also display cardiac abnormalities associated with heart failure (HF). Inflammation contributes to progressive renal dysfunction and increases cardiovascular mortality of patients with CKD. Interleukin (IL)-33 is a tissue-derived nuclear cytokine from the IL family. IL-33 constitutively expressed but upregulated and released after cellular damage or necrotic cell death, acting as a pro-inflammatory cytokine. We hypothesize that IL-33 plays a prominent mechanistic role in renal-cardio pathophysiology in CKD. Method We induced CKD in 10 pigs via bilateral renovascular disease and dyslipidemia. We developed a renally-targeted biopolymer-fused peptide inhibitor of nuclear-factor kappa (NF-k)B (ELP-p50i) and show it blocks NFkB activity in vitro and in vivo. NF-kB is a key pro-inflammatory transcription factor upregulated in CKD and closely interacts with IL-33. Pigs were observed for 6 weeks, renal (multi-detector CT) and cardiac structure and function (echo) were quantified, then randomized to single intra-renal ELP-p50i or placebo (n=5 each), and studies repeated 8 weeks later. Blood was collected to measure circulating TNF-α, IL-33 and its specific decoy receptor soluble (s) ST2 (ELISA). Heart weights were measured after euthanasia, and renal and cardiac expression of ST2 and morphometric analyses were performed. Results Loss of renal function in CKD was accompanied by increased heart weight, left ventricular (LV) hypertrophy, diastolic dysfunction, abnormal LV strain, renal/cardiac fibrosis, circulating TNF-α, IL-33 but unchanged sST2, and increased renal/cardiac ST2 expression. Most of these changes were improved after intra-renal ELP-p50i and accompanied by augmented sST2, suggesting that inhibition of renal inflammation can attenuate cardiac abnormalities via augmented clearance of IL-33 (Figure). Conclusion Our study supports a prominent role for renal inflammation as a driving force for precursors of HF in CKD, proposing a renal-cardio inflammatory axis possibly mediated by NF-kB-TNF-α-IL-33/ST2 interactions. TNF-α can stimulate IL-33 as IL33 can activate NF-kB and TNF-α, extending this inflammatory loop in both the kidney and heart. We show that a translational renal anti-inflammatory strategy via targeted inhibition of renal NFkB inhibits this axis and improves renal and cardiac function, which may guide to new treatments targeting renal inflammation in CKD.

Download Full-text

Trypanosoma cruzi Infection Induces Differential Modulation of Costimulatory Molecules and Cytokines by Monocytes and T Cells from Patients with Indeterminate and Cardiac Chagas' Disease

Infection and Immunity ◽

10.1128/iai.01931-06 ◽

2007 ◽

Vol 75 (4) ◽

pp. 1886-1894 ◽

Cited By ~ 64

Author(s):

Paulo E. A. Souza ◽

Manoel O. C. Rocha ◽

Cristiane A. S. Menezes ◽

Janete S. Coelho ◽

Andréa C. L. Chaves ◽

...

Keyword(s):

T Cells ◽

Trypanosoma Cruzi ◽

Chagas Disease ◽

Molecular Mechanisms ◽

Costimulatory Molecule ◽

Costimulatory Molecules ◽

Necrosis Factor Alpha ◽

Pathogenic Potential ◽

Indeterminate Form

ABSTRACT Interactions between macrophages and lymphocytes through costimulatory molecules and cytokines are essential for mounting an efficient immune response and controlling its pathogenic potential. Here we demonstrate the immunomodulatory capacity of Trypanosoma cruzi, the causative agent of Chagas' disease, through its ability to induce differential expression of costimulatory molecules and cytokines by monocytes and T cells. Costimulatory molecule and cytokine modulation was evaluated using cells from noninfected individuals and from patients with the asymptomatic indeterminate form and those with the severe cardiac clinical form of Chagas' disease. Our results show that while exposure of monocytes to live T. cruzi leads to an increase in the frequency of CD80+ monocytes in all groups, it decreases both the frequency and intensity of CD86 expression by monocytes from patients with the cardiac form but not from those with the indeterminate form. Conversely, exposure of lymphocytes to monocytes infected with T. cruzi increased the surface expression of cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) by T cells from indeterminate but not from cardiac patients, compared to that from control patients. These data suggest that T. cruzi induces a potentially down-regulatory environment in indeterminate subjects, which is associated with higher CD80 and CTLA-4 expression. To test the functional importance of this modulation, we evaluated the expression of cytokines after in vitro infection. Although exposure of lymphocytes to parasite-infected monocytes induced high expression of inflammatory and anti-inflammatory cytokines by T cells in all groups, indeterminate patients displayed a higher ratio of monocytes expressing interleukin 10 than tumor necrosis factor alpha following infection than did controls. These data show the ability of T. cruzi to actively change the expression of costimulatory molecules and cytokines, suggesting molecular mechanisms for the differential clinical evolution of human Chagas' disease.

Download Full-text

Blockade of KCa3.1 Attenuates Left Ventricular Remodeling after Experimental Myocardial Infarction

Cellular Physiology and Biochemistry ◽

10.1159/000430298 ◽

2015 ◽

Vol 36 (4) ◽

pp. 1305-1315 ◽

Cited By ~ 15

Author(s):

Chen-Hui Ju ◽

Xian-Pei Wang ◽

Chuan-Yu Gao ◽

Shuang-Xia Zhang ◽

Xing-Hua Ma ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Fibrosis ◽

Ventricular Remodeling ◽

Heart Function ◽

Left Ventricular Remodeling ◽

Left Ventricular ◽

Experimental Myocardial Infarction ◽

Ang Ii ◽

Pharmacological Blockade

Background/Aims: After myocardial infarction (MI), cardiac fibrosis greatly contributes to left ventricular remodeling and heart failure. The intermediate-conductance calcium-activated potassium Channel (KCa3.1) has been recently proposed as an attractive target of fibrosis. The present study aimed to detect the effects of KCa3.1 blockade on ventricular remodeling following MI and its potential mechanisms. Methods: Myocardial expression of KCa3.1 was initially measured in a mouse MI model by Western blot and real time-polymerase chain reaction. Then after treatment with TRAM-34, a highly selective KCa3.1 blocker, heart function and fibrosis were evaluated by echocardiography, histology and immunohistochemistry. Furthermore, the role of KCa3.1 in neonatal mouse cardiac fibroblasts (CFs) stimulated by angiotensin II (Ang II) was tested. Results: Myocardium expressed high level of KCa3.1 after MI. Pharmacological blockade of KCa3.1 channel improved heart function and reduced ventricular dilation and fibrosis. Besides, a lower prevalence of myofibroblasts was found in TRAM-34 treatment group. In vitro studies KCa3.1 was up regulated in CFs induced by Ang II and suppressed by its blocker.KCa3.1 pharmacological blockade attenuated CFs proliferation, differentiation and profibrogenic genes expression and may regulating through AKT and ERK1/2 pathways. Conclusion: Blockade of KCa3.1 is able to attenuate ventricular remodeling after MI through inhibiting the pro-fibrotic effects of CFs.

Download Full-text

Indeterminate form of Chagas disease: is left ventricular torsional mechanics a clue to subclinical myocardial abnormalities?

Journal of Echocardiography ◽

10.1007/s12574-016-0305-5 ◽

2016 ◽

Vol 15 (1) ◽

pp. 6-12 ◽

Cited By ~ 2

Author(s):

Marcio Silva Miguel Lima ◽

Mariana Callil Voos ◽

Wilson Mathias ◽

Jeane Mike Tsutsui

Keyword(s):

Chagas Disease ◽

Left Ventricular ◽

Indeterminate Form

Download Full-text

Interleukin-9 in Immunopathology of Trypanosoma cruzi Experimental Infection

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.756521 ◽

2021 ◽

Vol 11 ◽

Author(s):

Nadjania Saraiva de Lira Silva ◽

Cristina Mary Orikaza ◽

Fabiana Rodrigues de Santana ◽

Luana Aguiar dos Santos ◽

Bruno Ramos Salu ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Experimental Infection ◽

Cardiac Fibrosis ◽

Tissue Injury ◽

Chronic Phase ◽

Protective Role

Chagas’ disease is a parasitosis caused by Trypanosoma cruzi, which affects approximately 8 million people worldwide. The balance between pro- and anti-inflammatory cytokines produced during immunological responses contributes to disease prognosis and progression. Parasite tissue persistence can induce chronic inflammatory stimuli, which can cause long-term tissue injury and fibrosis. Chronic Chagas’ patients exhibit increased levels of interleukin (IL)-9, an important cytokine in the regulation of inflammatory and fibrogenic processes. Data on the role of IL-9 in other pathologies are sometimes contradictory, and few studies have explored this cytokine’s influence in Chagas’ disease pathology. Hence, the aim of this study was to evaluate the role of IL-9 in the progression of T. cruzi infection in vivo and in vitro. In vitro infection demonstrated that IL-9 reduced the number of infected cells and decreased the multiplication of intracellular amastigotes in both C2C12 myoblasts and bone marrow-derived macrophages. In myoblasts, the increased production of nitric oxide (NO) was essential for reduced parasite multiplication, whereas macrophage responses resulted in increased IL-6 and reduced TGF-β levels, indicating that parasite growth restriction mechanisms induced by IL-9 were cell-type specific. Experimental infection of BALB/c mice with T. cruzi trypomastigotes of the Y strain implicated a major role of IL-9 during the chronic phase, as increased Th9 and Tc9 cells were detected among splenocytes; higher levels of IL-9 in these cell populations and increased cardiac IL-9 levels were detected compared to those of uninfected mice. Moreover, rIL9 treatment decreased serum IL-12, IL-6, and IL-10 levels and cardiac TNF-α levels, possibly attempting to control the inflammatory response. IL-9 neutralization increased cardiac fibrosis, synthesis of collagens I and III, and mastocyte recruitment in BALB/c heart tissue during the chronic phase. In conclusion, our data showed that IL-9 reduced the invasion and multiplication of T. cruzi in vitro, in both myoblasts and macrophages, favoring disease control through cell-specific mechanisms. In vivo, IL-9 was elevated during experimental chronic infection in BALB/c mice, and this cytokine played a protective role in the immunopathological response during this phase by controlling cardiac fibrosis and proinflammatory cytokine production.

Download Full-text

Cholinergic Elicitation Prevents Ventricular Remodeling via Alleviations of Myocardial Mitochondrial Injury Linked to Inflammation in Ischemia-Induced Chronic Heart Failure Rats

Mediators of Inflammation ◽

10.1155/2021/4504431 ◽

2021 ◽

Vol 2021 ◽

pp. 1-17

Author(s):

Yang Zhao ◽

Huaxin Sun ◽

Kai Li ◽

Luxiang Shang ◽

Xiaoyan Liang ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Cardiac Fibrosis ◽

Ventricular Remodeling ◽

Left Ventricular ◽

H9c2 Cells ◽

Tnf Α ◽

Underlying Mechanisms

Background. Cholinergic anti-inflammatory pathway (CAP) is implicated in cardioprotection in chronic heart failure (CHF) by downregulating inflammation response. Mitochondrial injuries play an important role in ventricular remodeling of the CHF process. Herein, we aim to investigate whether CAP elicitation prevents ventricular remodeling in CHF by protecting myocardial mitochondrial injuries and its underlying mechanisms. Methods and Results. CHF models were established by ligation of anterior descending artery for 5 weeks. Postoperative survival rats were assigned into 5 groups: the sham group (sham, n = 10 ), CHF group (CHF, n = 11 ), Vag group (CHF+vagotomy, n = 10 ), PNU group (CHF+PNU-282987 for 4 weeks, n = 11 ), and Vag+PNU group (CHF+vagotomy+PNU-282987 for 4 weeks, n = 10 ). The antiventricular remodeling effect of cholinergic elicitation was evaluated in vivo, and H9C2 cells were selected for the TNF-α gradient stimulation experiment in vitro. In vivo, CAP agitated by PNU-282987 alleviated the left ventricular dysfunction and inhibited the energy metabolism remodeling. Further, cholinergic elicitation increased myocardium ATP levels and reduced systemic inflammation. CAP induction alleviates macrophage infiltration and cardiac fibrosis, of which the effect is counteracted by vagotomy. Myocardial mitochondrial injuries were ameliorated by CAP activation, including the reserved ultrastructural integrity, declining ROS overload, reduced myocardial apoptosis, and enhanced mitochondrial fusion. In vitro, TNF-α intervention significantly exacerbated the mitochondrial damage in H9C2 cells. Conclusion. CAP elicitation effectively improves ischemic ventricular remodeling by suppressing systemic and cardiac inflammatory response, attenuating cardiac fibrosis and potentially alleviating the mitochondrial dysfunction linked to hyperinflammation reaction.

Download Full-text

Activation of SIRT1 by Resveratrol Alleviates Pressure Overload-Induced Cardiac Hypertrophy via Suppression of TGF-β1 Signaling

Pharmacology ◽

10.1159/000518464 ◽

2021 ◽

pp. 1-15

Author(s):

Yong Chen ◽

Ting He ◽

Zhongjun Zhang ◽

Junzhi Zhang

Keyword(s):

Cardiac Hypertrophy ◽

Protective Effect ◽

Signaling Pathway ◽

Cardiac Fibrosis ◽

Pressure Overload ◽

Left Ventricular ◽

Neonatal Rat ◽

Ang Ii ◽

Tgf Β1

Introduction: Silent information regulator 1 (SIRT1) has been extensively investigated in the cardiovascular system and has been shown to play a pivotal role in mediating cell death/survival, energy production, and oxidative stress. However, the functional role of SIRT1 in pressure overload-induced cardiac hypertrophy and dysfunction remains unclear. Resveratrol (Rsv), a widely used activator of SIRT1, has been reported to protect against cardiovascular disease. We here examine whether activation of SIRT1 by Rsv attenuate pressure overload-induced cardiac hypertrophy and to identify the underlying molecular mechanisms. Methods: In vivo, rat model of pressure overload-induced myocardial hypertrophy was established by abdominal aorta constriction (AAC) procedure. In vitro, Angiotensin II (Ang II) was applied to induce hypertrophy in cultured neonatal rat cardiomyocytes (NCMs). Hemodynamics and histological analyses of the heart were evaluated. The expression of SIRT1, transforming growth factor-β1 (TGF-β1)/phosphorylated (p)-small mother against decapentaplegic (Smad)3 and hypertrophic markers were determined by immunofluorescence, real-time PCR, and Western blotting techniques. Results: In the current study, Rsv treatment improved left ventricular function and reduced left ventricular hypertrophy and cardiac fibrosis significantly in the pressure overload rats. The expression of SIRT1 was significantly reduced, while the expression of TGF-β1/p-Smad3 was significantly enhanced in AAC afflicted rat heart. Strikingly, treatment with Rsv restored the expressions of SIRT1 and TGF-β1/p-Smad3 under AAC influence. However, SIRT1 inhibitor Sirtinol (Snl) markedly prevented the effects of Rsv, which suggest that SIRT1 signaling pathway was involved in the cardiac protective effect of Rsv. In vitro studies performed in Ang II-induced hypertrophy in NCMs confirmed the cardiac protective effect of Rsv. Furthermore, the study presented that SIRT1 negatively correlated with the cardiac hypertrophy, cardiac fibrosis, and the TGF-β1/p-Smad3 expression. Conclusions: Taken together, these results indicated that activation of SIRT1 by Rsv attenuates cardiac hypertrophy, cardiac fibrosis, and improves cardiac function possibly via regulation of the TGF-β1/p-Smad3 signaling pathway. Our study may provide a potential therapeutic strategy for cardiac hypertrophy.

Download Full-text