Ouabain prevents pathological cardiac hypertrophy and heart failure through activation of phosphoinositide 3-kinase α in mouse

Abstract Aims Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.

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Bone morphogenetic protein-4: a novel therapeutic target for pathological cardiac hypertrophy/heart failure

Heart Failure Reviews ◽

10.1007/s10741-014-9429-8 ◽

2014 ◽

Vol 19 (6) ◽

pp. 781-788 ◽

Cited By ~ 11

Author(s):

Wen-Ting Guo ◽

De-Li Dong

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Bone Morphogenetic Protein ◽

Therapeutic Target ◽

Bone Morphogenetic Protein 4 ◽

Pathological Cardiac Hypertrophy ◽

Morphogenetic Protein ◽

Novel Therapeutic

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Phosphoinositide-3 Kinase Signaling in Cardiac Hypertrophy and Heart Failure

Current Pharmaceutical Design ◽

10.2174/138161211796390976 ◽

2011 ◽

Vol 17 (18) ◽

pp. 1818-1824 ◽

Cited By ~ 108

Author(s):

Toshinori Aoyagi ◽

Takashi Matsui

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Kinase Signaling ◽

Phosphoinositide 3 Kinase

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

Bioscience Reports ◽

10.1042/bsr20200661 ◽

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.

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

10.1101/2021.03.19.434301 ◽

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.

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Role of CyPA in cardiac hypertrophy and remodeling

Bioscience Reports ◽

10.1042/bsr20193190 ◽

2019 ◽

Vol 39 (12) ◽

Cited By ~ 1

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.

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Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

Biological Research ◽

10.1186/s40659-021-00342-6 ◽

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

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Novel genomic targets of valosin-containing protein in protecting pathological cardiac hypertrophy

Scientific Reports ◽

10.1038/s41598-020-75128-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Ning Zhou ◽

Xin Chen ◽

Jing Xi ◽

Ben Ma ◽

Christiana Leimena ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Molecular Mechanisms ◽

Pressure Overload ◽

Bioinformatic Analysis ◽

Pathological Cardiac Hypertrophy ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation ◽

Survival Signaling ◽

G Protein Coupled

Abstract Pressure overload-induced cardiac hypertrophy, such as that caused by hypertension, is a key risk factor for heart failure. However, the underlying molecular mechanisms remain largely unknown. We previously reported that the valosin-containing protein (VCP), an ATPase-associated protein newly identified in the heart, acts as a significant mediator of cardiac protection against pressure overload-induced pathological cardiac hypertrophy. Still, the underlying molecular basis for the protection is unclear. This study used a cardiac-specific VCP transgenic mouse model to understand the transcriptomic alterations induced by VCP under the cardiac stress caused by pressure overload. Using RNA sequencing and comprehensive bioinformatic analysis, we found that overexpression of the VCP in the heart was able to normalize the pressure overload-stimulated hypertrophic signals by activating G protein-coupled receptors, particularly, the olfactory receptor family, and inhibiting the transcription factor controlling cell proliferation and differentiation. Moreover, VCP overexpression restored pro-survival signaling through regulating alternative splicing alterations of mitochondrial genes. Together, our study revealed a novel molecular regulation mediated by VCP under pressure overload that may bring new insight into the mechanisms involved in protecting against hypertensive heart failure.

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Analysis of Drosophila cardiac hypertrophy by micro-computerized tomography for genetic dissection of heart growth mechanisms

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00387.2021 ◽

2021 ◽

Author(s):

Courtney E Petersen ◽

Benjamin A Tripoli ◽

Todd A Schoborg ◽

Jeremy T Smyth

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Computerized Tomography ◽

Genetic Model ◽

Genetic Dissection ◽

Molecular Signaling ◽

Pathological Cardiac Hypertrophy ◽

Underlying Mechanisms ◽

Microct Analysis ◽

Constitutively Active

Heart failure is often preceded by pathological cardiac hypertrophy, a thickening of the heart musculature driven by complex gene regulatory and signaling processes. The Drosophila heart has great potential as a genetic model for deciphering the underlying mechanisms of cardiac hypertrophy. However, current methods for evaluating hypertrophy of the Drosophila heart are laborious and difficult to carry out reproducibly. Here we demonstrate that micro-computerized tomography (microCT) is an accessible, highly reproducible method for non-destructive, quantitative analysis of Drosophila heart morphology and size. To validate our microCT approach for analyzing Drosophila cardiac hypertrophy, we show that expression of constitutively active Ras (Ras85DV12), previously shown to cause hypertrophy of the fly heart, results in significant thickening of both adult and larval heart walls when measured from microCT images. We then show using microCT analysis that genetic upregulation of store-operated Ca2+ entry (SOCE) driven by expression of constitutively active Stim (StimCA) or Orai (OraiCA) proteins also results in significant hypertrophy of the Drosophila heart, through a process that specifically depends on Orai Ca2+ influx channels. Intravital imaging of heart contractility revealed significantly reduced end diastolic and systolic dimensions in StimCA and OraiCA expressing hearts, consistent with the hypertrophic phenotype. These results demonstrate that increased SOCE activity is an important driver of hypertrophic cardiomyocyte growth, and demonstrate how microCT analysis combined with tractable genetic tools in Drosophila can be used to delineate molecular signaling processes that underlie cardiac hypertrophy and heart failure.

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

Circulation ◽

10.1161/circ.142.suppl_3.16205 ◽

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.

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