scholarly journals Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis

2021 ◽  
Author(s):  
Zhiyu Dai ◽  
Jianding Cheng ◽  
Bin Liu ◽  
Dan Yi ◽  
Anlin Feng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Adaptive Responses ◽  
Genetic Ablation ◽  
Pathological Cardiac Hypertrophy ◽  
And Function

Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure remains elusive. We observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Mice with Tie2-Cre-mediated deletion of Egln1 (encoding PHD2) or tamoxifen-induced endothelial Egln1 deletion exhibited left ventricular hypertrophy and cardiac fibrosis. Genetic ablation and pharmacological inhibition of Hif2a but not Hif1a in endothelial Egln1 deficient mice normalized cardiac size and function. The present studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in a HIF-2α dependent manner. Targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

scholarly journals Sophoricoside ameliorates cardiac hypertrophy by activating AMPK/mTORC1-mediated autophagy

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Maomao Gao ◽  
Fengjiao Hu ◽  
Manli Hu ◽  
Yufeng Hu ◽  
Hongjie Shi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Dependent Manner ◽  
Protective Effects ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy ◽  
Compound C

Abstract Aim: The study aims to evaluate protective effects of sophoricoside (Sop) on cardiac hypertrophy. Meanwhile, the potential and significance of Sop should be broadened and it should be considered as an attractive drug for the treatment of pathological cardiac hypertrophy and heart failure. Methods: Using the phenylephrine (PE)-induced neonatal rat cardiomyocytes (NRCMs) enlargement model, the potent protection of Sop against cardiomyocytes enlargement was evaluated. The function of Sop was validated in mice received transverse aortic coarctation (TAC) or sham surgery. At 1 week after TAC surgery, mice were treated with Sop for the following 4 weeks, the hearts were harvested after echocardiography examination. Results: Our study revealed that Sop significantly mitigated TAC-induced heart dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis. Mechanistically, Sop treatment induced a remarkable activation of AMPK/mTORC1-autophagy cascade following sustained hypertrophic stimulation. Importantly, the protective effect of Sop was largely abolished by the AMPKα inhibitor Compound C, suggesting an AMPK activation-dependent manner of Sop function on suppressing pathological cardiac hypertrophy. Conclusion: Sop ameliorates cardiac hypertrophy by activating AMPK/mTORC1-mediated autophagy. Hence, Sop might be an attractive candidate for the treatment of pathological cardiac hypertrophy and heart failure.

scholarly journals Loss of Endothelial Hypoxia Inducible Factor‐Prolyl Hydroxylase 2 Induces Cardiac Hypertrophy and Fibrosis

2021 ◽  
Author(s):  
Zhiyu Dai ◽  
Jianding Cheng ◽  
Bin Liu ◽  
Dan Yi ◽  
Anlin Feng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Endothelial Cells ◽  
Left Ventricular Hypertrophy ◽  
Cardiac Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Hypoxia Inducible Factor ◽  
Left Ventricular ◽  
Sequencing Analysis ◽  
Dependent Manner

Background Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial PHD2 (prolyl‐4 hydroxylase 2)/hypoxia inducible factor (HIF) signaling in the pathogenesis of cardiac hypertrophy and heart failure remains elusive. Methods and Results Mice with Egln1 Tie2Cre ( Tie2 ‐Cre‐mediated deletion of Egln1 [encoding PHD2]) exhibited left ventricular hypertrophy evident by increased thickness of anterior and posterior wall and left ventricular mass, as well as cardiac fibrosis. Tamoxifen‐induced endothelial Egln1 deletion in adult mice also induced left ventricular hypertrophy and fibrosis. Additionally, we observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Moreover, genetic ablation of Hif2a but not Hif1a in Egln1 Tie2Cre mice normalized cardiac size and function. RNA sequencing analysis also demonstrated HIF‐2α as a critical mediator of signaling related to cardiac hypertrophy and fibrosis. Pharmacological inhibition of HIF‐2α attenuated cardiac hypertrophy and fibrosis in Egln1 Tie2Cre mice. Conclusions The present study defines for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in an HIF‐2α–dependent manner. PHD2 was markedly decreased in cardiovascular endothelial cells in patients with cardiomyopathy. Thus, targeting PHD2/HIF‐2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

Abstract 13810: TT-00920, a Clinical Stage Novel Phosphodiesterase 9 Inhibitor, Protects Against Heart Failure in a Rat Model of Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zejuan Sheng ◽  
Xiaoyan Qiang ◽  
Guoyu Li ◽  
Huimin Wang ◽  
Wenxin Dong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Rat Model ◽  
Cardiac Fibrosis ◽  
Clinical Stage ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Therapeutic Effects ◽  
Dependent Manner

Introduction: Phosphodiesterase 9 (PDE9) controls natriuretic-peptide-stimulated cyclic guanosine monophosphate in cardiac myocytes and is stongly upregulated in human heart failure, suggesting its potential as a promising therapeutic target in heart failure. Here we investigated the potential effects of TT-00920, a clinical stage novel and highly selective PDE9 inhibitor, on heart failure in a rat model of myocardial infarction. Methods: Myocardial infarction was induced by left anterior descending coronary artery (LAD) ligation in male Sprague Dawley rats. After 4-week treatment of vehicle, LCZ696, TT-00920, or TT-00920/Valsartan by oral gavage, efficacy was assessed by echocardiography and cardiac histopathology. Results: TT-00920 had remarkably improved cardiac function, protected against cardiac remodeling and fibrosis in a dose-dependent manner. TT-00920/Valsartan combination showed superior beneficial efficacy when compared to TT-00920 or LCZ696 single agent.Figure 1. TT-00920 improved cardiac function and ventricular remodeling.Figure 2. TT-00920 attenuated cardiac fibrosis in peri-infarct zone. Conclusions: TT-00920 reversed LAD-induced left ventricular dysfunction and remodeling, supporting its potential as a novel therapeutic agent for heart failure. The superior efficacy of TT-00920/Valsartan combination suggests that TT-00920 and renin-angiotensin-aldosterone system inhibitors may have additive therapeutic effects in heart failure.TT-00920 is currently being evaluated in Phase 1 clinical study for safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers (NCT04364789).

scholarly journals Role of CyPA in cardiac hypertrophy and remodeling

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Mengfei Cao ◽  
Wei Yuan ◽  
Meiling Peng ◽  
Ziqi Mao ◽  
Qianru Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Interstitial Fibrosis ◽  
Systolic Function ◽  
Cardiac Fibroblasts ◽  
Cardiomyocyte Hypertrophy ◽  
Pathological Cardiac Hypertrophy ◽  
Complex Process

Abstract Pathological cardiac hypertrophy is a complex process and eventually develops into heart failure, in which the heart responds to various intrinsic or external stress, involving increased interstitial fibrosis, cell death and cardiac dysfunction. Studies have shown that oxidative stress is an important mechanism for this maladaptation. Cyclophilin A (CyPA) is a member of the cyclophilin (CyPs) family. Many cells secrete CyPA to the outside of the cells in response to oxidative stress. CyPA from blood vessels and the heart itself participate in a variety of signaling pathways to regulate the production of reactive oxygen species (ROS) and mediate inflammation, promote cardiomyocyte hypertrophy and proliferation of cardiac fibroblasts, stimulate endothelial injury and vascular smooth muscle hyperplasia, and promote the dissolution of extracellular matrix (ECM) by activating matrix metalloproteinases (MMPs). The events triggered by CyPA cause a decline of diastolic and systolic function and finally lead to the occurrence of heart failure. This article aims to introduce the role and mechanism of CyPA in cardiac hypertrophy and remodeling, and highlights its potential role as a disease biomarker and therapeutic target.

scholarly journals Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

2021 ◽  
Vol 54 (1) ◽  
Author(s):  
Manuel Ramos-Kuri ◽  
Sri Harika Meka ◽  
Fabio Salamanca-Buentello ◽  
Roger J. Hajjar ◽  
Larissa Lipskaia ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein Kinase ◽  
Cardiac Hypertrophy ◽  
Mapk Pathway ◽  
Therapeutic Targets ◽  
Cardiac Diseases ◽  
Ras Genes ◽  
Septal Defects ◽  
Pathological Cardiac Hypertrophy

Abstract The Ras family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) represents one of the main components of intracellular signal transduction required for normal cardiac growth, but is also critically involved in the development of cardiac hypertrophy and heart failure. The present review provides an update on the role of the H-, K- and N-Ras genes and their related pathways in cardiac diseases. We focus on cardiac hypertrophy and heart failure, where Ras has been studied the most. We also review other cardiac diseases, like genetic disorders related to Ras. The scope of the review extends from fundamental concepts to therapeutic applications. Although the three Ras genes have a nearly identical primary structure, there are important functional differences between them: H-Ras mainly regulates cardiomyocyte size, whereas K-Ras regulates cardiomyocyte proliferation. N-Ras is the least studied in cardiac cells and is less associated to cardiac defects. Clinically, oncogenic H-Ras causes Costello syndrome and facio-cutaneous-skeletal syndromes with hypertrophic cardiomyopathy and arrhythmias. On the other hand, oncogenic K-Ras and alterations of other genes of the Ras-Mitogen-Activated Protein Kinase (MAPK) pathway, like Raf, cause Noonan syndrome and cardio-facio-cutaneous syndromes characterized by cardiac hypertrophy and septal defects. We further review the modulation by Ras of key signaling pathways in the cardiomyocyte, including: (i) the classical Ras-Raf-MAPK pathway, which leads to a more physiological form of cardiac hypertrophy; as well as other pathways associated with pathological cardiac hypertrophy, like (ii) The SAPK (stress activated protein kinase) pathways p38 and JNK; and (iii) The alternative pathway Raf-Calcineurin-Nuclear Factor of Activated T cells (NFAT). Genetic alterations of Ras isoforms or of genes in the Ras-MAPK pathway result in Ras-opathies, conditions frequently associated with cardiac hypertrophy or septal defects among other cardiac diseases. Several studies underline the potential role of H- and K-Ras as a hinge between physiological and pathological cardiac hypertrophy, and as potential therapeutic targets in cardiac hypertrophy and failure. Graphic abstract

Abstract 16205: MKP-5 Deficiency Attenuates Pressure Overload-induced Cardiac Hypertrophy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kisuk Min ◽  
Yan Huang ◽  
Frank J Giordano ◽  
Sudip Bajpeyi ◽  
Anton M Bennett
Keyword(s):  
Heart Failure ◽  
Body Weight ◽  
Cardiac Hypertrophy ◽  
Cardiac Muscle ◽  
Molecular Mechanisms ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Body Weight Ratio ◽  
Pathological Cardiac Hypertrophy

Introduction: Cardiac remodeling occurs in response to pathological stimuli including chronic pressure overload, subsequently leading to heart failure. Despite considerable research efforts, the molecular mechanisms responsible for heart failure have yet to be fully elucidated. One of the prominent signaling pathways involved in the development of pathological cardiac hypertrophy is the mitogen-activated protein kinases (MAPKs) pathways. The MAPKs are inactivated by the MAPK phosphatases (MKPs) through direct dephosphorylation. Growing evidence suggests the importance of MKP-5 signaling mechanisms in physiological and pathological processes. However, the role of MKP-5 has not been explored in cardiac muscle. The objective of this study is to investigate how MKP-5-mediated MAPK activity contributes to mechanisms responsible for pressure overload-induced cardiac hypertrophy. Hypothesis: We tested the hypothesis that MKP-5 serves as a central regulator of MAPKs in pressure overload-induced cardiac hypertrophy. Methods: To investigate the role of MKP-5 in cardiac muscle, we caused pressure overload-induced cardiac hypertrophy in wild type (mkp-5 +/+ ) mice and MKP-5 deficient mice (mkp-5 -/- ) through transverse aortic constriction (TAC). Cardiac function was evaluated by echocardiographic analysis at 4 weeks after TAC. Cardiac hypertrophy was measured by heart-to-body weight ratio. Interstitial myocardial fibrosis was evaluated by Sirius red stains and expression of fibrogenic genes was determined by quantitative PCR. Results: Echocardiographic analysis showed that the ejection fraction and fractional shortening of mkp-5 +/+ mice significantly decreased by at 4 weeks after TAC. Heart-to-body weight ratio increased in mkp-5 +/+ mice. However, MKP-5-deficient heart was protected from cardiac dysfunction and cardiac hypertrophy induced by TAC. Importantly, the fibrogenic genes were markedly reduced in mkp-5 -/- mice as compared with mkp-5 +/+ mice at 4 weeks after TAC. Conclusions: Collectively, our study demonstrates that MKP-5 deficiency prevents the heart from pressure overload-induced cardiac hypertrophy and suggests that MKP-5 may serve as a novel therapeutic target for treatment of heart disease.

Abstract 119: Targeting Cardiac Hypertrophy with Small Molecule Inhibitors of JMJD2A

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Qing-jun Zhang ◽  
Ganesha Rai ◽  
Ajit Jadhav ◽  
Anton Simeonov ◽  
David Maloney ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Enzymatic Activity ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Epigenetic Modification ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Innovative Drug ◽  
Pathological Cardiac Hypertrophy

One of the major challenges in managing and treating heart failure patients is to develop disease-modifying drugs that can prevent, reverse, or slow down the disease progression. Upon pathological insults, the heart undergoes remodeling processes, including left ventricular hypertrophy and reprogramming of gene expression. Understanding the mechanisms involved could provide a key to develop interventional therapeutics. Epigenetic modification of chromatin, including histone methylation, regulates gene transcription in response to environmental signals. JMJD2A is a trimethyl-lysine specific histone lysine demethylase. To study the role of JMJD2A, we generated heart specific JMJD2A overexpression and deletion mouse lines. Our studies with these genetically modified mice indicated that JMJD2A is required for pathological cardiac hypertrophy. Furthermore, we show that the demethylase activity of JMJD2A is required for its transcriptional activity. These data suggests that targeting JMJD2A enzymatic activity may be used to suppress hypertrophic remodeling. To test this hypothesis, we tested a collection of small molecule inhibitors of JMJD2 in collaboration with Chemists in NIH and identified several small molecule inhibitors of JMJD2A that are active in cell-based assays. These small molecule inhibitors of JMJD2A inhibited the phenylephrine-stimulated cardiomyocyte hypertrophy in vitro. Our data suggests that JMJD2A enzymatic activity may act as a hypertrophic determinant and may be an innovative drug target for prevention and treatment of pathological cardiac hypertrophy and heart failure.

scholarly journals Phosphodiesterase 2 inhibition preferentially promotes NO/guanylyl cyclase/cGMP signaling to reverse the development of heart failure

2018 ◽  
Vol 115 (31) ◽  
pp. E7428-E7437 ◽  
Author(s):  
Reshma S. Baliga ◽  
Michael E. J. Preedy ◽  
Matthew S. Dukinfield ◽  
Sandy M. Chu ◽  
Aisah A. Aubdool ◽  
...  
Keyword(s):  
Heart Failure ◽  
Guanylyl Cyclase ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Treatment Modalities ◽  
Pharmacodynamic Profile ◽  
Cgmp Signaling ◽  
Synthase Inhibitor ◽  
And Function

Heart failure (HF) is a shared manifestation of several cardiovascular pathologies, including hypertension and myocardial infarction, and a limited repertoire of treatment modalities entails that the associated morbidity and mortality remain high. Impaired nitric oxide (NO)/guanylyl cyclase (GC)/cyclic guanosine-3′,5′-monophosphate (cGMP) signaling, underpinned, in part, by up-regulation of cyclic nucleotide-hydrolyzing phosphodiesterase (PDE) isozymes, contributes to the pathogenesis of HF, and interventions targeted to enhancing cGMP have proven effective in preclinical models and patients. Numerous PDE isozymes coordinate the regulation of cardiac cGMP in the context of HF; PDE2 expression and activity are up-regulated in experimental and human HF, but a well-defined role for this isoform in pathogenesis has yet to be established, certainly in terms of cGMP signaling. Herein, using a selective pharmacological inhibitor of PDE2, BAY 60-7550, and transgenic mice lacking either NO-sensitive GC-1α (GC-1α−/−) or natriuretic peptide-responsive GC-A (GC-A−/−), we demonstrate that the blockade of PDE2 promotes cGMP signaling to offset the pathogenesis of experimental HF (induced by pressure overload or sympathetic hyperactivation), reversing the development of left ventricular hypertrophy, compromised contractility, and cardiac fibrosis. Moreover, we show that this beneficial pharmacodynamic profile is maintained in GC-A−/− mice but is absent in animals null for GC-1α or treated with a NO synthase inhibitor, revealing that PDE2 inhibition preferentially enhances NO/GC/cGMP signaling in the setting of HF to exert wide-ranging protection to preserve cardiac structure and function. These data substantiate the targeting of PDE2 in HF as a tangible approach to maximize myocardial cGMP signaling and enhancing therapy.

Platycodin D Reverses Pathological Cardiac Hypertrophy and Fibrosis in Spontaneously Hypertensive Rats

2018 ◽  
Vol 46 (03) ◽  
pp. 537-549 ◽  
Author(s):  
Yuan-Chuan Lin ◽  
Yu-Chen Lin ◽  
Wei-Wen Kuo ◽  
Chia-Yao Shen ◽  
Yi-Chang Cheng ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Histopathological Examination ◽  
Biological Effects ◽  
Left Ventricular ◽  
Internal Diameter ◽  
Spontaneously Hypertensive ◽  
Platycodin D ◽  
Concentric Hypertrophy ◽  
Pathological Cardiac Hypertrophy

Platycodin D (PD) is the main active saponin isolated from Platycodon grandiflorum (PG) and is reported to exhibit anticancer, anti-angiogenic, anti-inflammation and anti-obesity biological effects. The current study aims to evaluate the therapeutic efficacy of PD in cardiac fibrosis and for hypertrophy in spontaneous hypertension rats (SHRs) and to verify inhibition of the signaling pathway. Significant increases in the cardiac functional indices of left ventricular internal diameter end diastole (LVIDd) and left ventricular internal diameter end systole (LVIDs); the eccentric hypertrophy marker p-MEK5; concentric hypertrophy markers, such as CaMKII[Formula: see text] and calcineurin; and expression levels of NFATc3, p-GATA4 and BNP were observed in spontaneously hypertensive groups. PD treatment reversed these increases in SHRs. In addition, an increase in the fibrosis markers FGF2, uPA, MMP2, MMP9, TGF[Formula: see text]-1 and CTGF during cardiac hypertrophy was detected by western blotting analyses. These results demonstrated that PD treatment considerably attenuates cardiac fibrosis. Histopathological examination revealed that PD treatment remarkably reduced collagen accumulation in contrast to spontaneously hypertensive groups. This study clearly suggests that PD provides myocardial protection by alleviating two damaging responses to hypertension, fibrosis and hypertrophy, in the heart.

Abstract P140: Mutant Mice Carrying Global Loss Of Npr1 Exhibit Cardiac Fibrosis, Hypertrophy, And Congestive Heart Failure: Implication Of TGF-Beta/SMAD Signaling Pathway

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Chandramohan Ramasamy ◽  
Umadevi Subramanian ◽  
Kailash N Pandey
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Growth Factor ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Mutant Mice ◽  
Null Mutant ◽  
Wild Type

The cardiac hormones, atrial and brain natriuretic peptides (ANP and BNP) bind to natriuretic peptide receptor-A (NPRA), which synthesizes the second messenger cGMP. The objective of this study was to determine the underlying mechanisms that regulate the development of cardiac hypertrophy, fibrosis, and congestive heart failure (CHF) in Npr1 (encoding NPRA) gene-knockout mice. The Npr1 null mutant ( Npr1 -/- , 0-copy), heterozygous ( Npr1 +/- , 1-copy), and wild-type ( Npr1 +/+ , 2-copy) mice were orally administered with transforming growth factor-β1 receptor I (TGF-β1R1) antagonist, GW788388 (2 mg/kg/day) by oral gavage for 28 days. The left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVEDS), posterior wall thickness (PWT), and percent fractional shortening (FS) were analyzed by echocardiography. The heart was isolated and used for the analysis of fibrotic markers using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot methods. The heart weight-to-body weight (HW/BW) ratio, LVEDD, LVEDS and PWT were significantly (p<0.005) increased in Npr1 -/- and Npr1 +/- mice than wild-type Npr1 +/+ mice. The FS was greatly reduced in Npr1 -/- and Npr1 +/- mice compared with Npr1 +/+ mice. The Npr1 -/- null mutant (0-copy) mice showed 52% increase in HW/BW ratio and 6-fold induction of cardiac fibrosis as compared with 2-copy control mice. The cardiac expression of fibrotic markers including collagen-1a (COL-1a; 3.5-fold), connective tissue growth factor (CTGF; 5-fold), α-smooth muscle actin (α-SMA; 4-fold), TGF-β1RI (4-fold), TGF-β1RII (3.5-fold), and SMAD-2/3 proteins (3-to-5 fold) were significantly increased in Npr1 -/- and Npr1 +/- mutant mice compared with age-matched Npr1 +/+ animals. The treatment with TGF-β1R1 antagonist, significantly (p<0.001) prevented the cardiac hypertrophy, fibrosis, CHF, and down-regulated the expression of fibrotic markers and SMAD proteins in mutant mice. The LVEDD, LVEDS, and FS were significantly (p<0.001) improved in the drug treated Npr1 -/- mice. The present results indicate that the cardiac hypertrophy, fibrosis, and CHF in Npr1 mutant mice is regulated through the TGF-β1-mediated SMAD-dependent signaling pathway.

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