Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy

Introduction: E193, a truncating mutation in the transcription cofactor Eyes absent 4 (Eya4) causes hearing impairment followed by heart failure. Here we identified the Eya4 dependent molecular mechanisms leading to the cardiac phenotype in the E193 mutation. Methods and Results: First we showed in vitro that the cyclin-dependent kinase inhibitor protein p27kip1 is a direct target of Eya4/Six1 and is suppressed upon Eya4 overexpression, whereas E193 has a dominant negative effect, releasing Eya4 mediated suppression of p27. We next generated transgenic mice with cardiac specific constitutive overexpression of full-length Eya4 or the mutant form E193. While E193 transgenic mice developed age-dependent DCM, Eya4 mice displayed cardiac hypertrophy already under basal conditions as judged by increases in heart weight and cardiomyocyte cross-sectional areas along with increases in myocardial dimension and mass. These two distinct cardiac phenotypes were even more aggravated upon pressure overload suggesting Eya4 is a regulator of cardiac hypertrophy. We also observed that the activity of Casein Kinase 2-α and the phosphorylation status of HDAC2 were significantly upregulated in the Eya4 transgenic mice, while they were significantly reduced in E193 mice, under baseline conditions and pressure overload. We were also able to identify a new human mutation (E215) with a phenotype comparable to the one seen in E193 patients. Conclusion: Our results implicate that Eya4/Six1 regulates cardiac hypertrophic reactions via p27/CK2-α/HDAC2 and indicate that truncating mutations in Eya4 interfere with this newly established signalling pathway.

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A peptide of the N terminus of GRK5 attenuates pressure-overload hypertrophy and heart failure

Science Signaling ◽

10.1126/scisignal.abb5968 ◽

2021 ◽

Vol 14 (676) ◽

pp. eabb5968

Author(s):

Ryan C. Coleman ◽

Akito Eguchi ◽

Melissa Lieu ◽

Rajika Roy ◽

Eric W. Barr ◽

...

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Cardiac Hypertrophy ◽

G Protein ◽

Cardiac Fibrosis ◽

Ventricular Remodeling ◽

Pressure Overload ◽

Nuclear Accumulation ◽

Nuclear Targeting ◽

Amino Terminal

Aberrant changes in gene expression underlie the pathogenesis and progression of pressure-overload heart failure, leading to maladaptive cardiac hypertrophy, ventricular remodeling, and contractile dysfunction. Signaling through the G protein Gq triggers maladaptation and heart failure, in part through the activation of G protein–coupled receptor kinase 5 (GRK5). Hypertrophic stimuli induce the accumulation of GRK5 in the nuclei of cardiomyocytes, where it regulates pathological gene expression through multiple transcription factors including NFAT. The nuclear targeting of GRK5 is mediated by an amino-terminal (NT) domain that binds to calmodulin (CaM). Here, we sought to prevent GRK5-mediated pathology in pressure-overload maladaptation and heart failure by expressing in cardiomyocytes a peptide encoding the GRK5 NT (GRK5nt) that encompasses the CaM binding domain. In cultured cardiomyocytes, GRK5nt expression abrogated Gq-coupled receptor–mediated hypertrophy, including attenuation of pathological gene expression and the transcriptional activity of NFAT and NF-κB. We confirmed that GRK5nt bound to and blocked Ca2+-CaM from associating with endogenous GRK5, thereby preventing GRK5 nuclear accumulation after pressure overload. We generated mice that expressed GRKnt in a cardiac-specific fashion (TgGRK5nt mice), which exhibited reduced cardiac hypertrophy, ventricular dysfunction, pulmonary congestion, and cardiac fibrosis after chronic transverse aortic constriction. Together, our data support a role for GRK5nt as an inhibitor of pathological GRK5 signaling that prevents heart failure.

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Hydroxysafflor yellow A attenuates left ventricular remodeling after pressure overload-induced cardiac hypertrophy in rats

Pharmaceutical Biology ◽

10.3109/13880209.2013.805791 ◽

2013 ◽

Vol 52 (1) ◽

pp. 31-35 ◽

Cited By ~ 16

Author(s):

Jianping Wang ◽

Qing Zhang ◽

Xiuhua Mei ◽

Xiuzhen Zhang

Keyword(s):

Cardiac Hypertrophy ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Pressure Overload ◽

Left Ventricular ◽

Hydroxysafflor Yellow A

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Superoxide scavenging and Akt inhibition in myocardium ameliorate pressure overload-induced NF-κB activation and cardiac hypertrophy

Physiological Genomics ◽

10.1152/physiolgenomics.00202.2009 ◽

2010 ◽

Vol 41 (2) ◽

pp. 127-136 ◽

Cited By ~ 11

Author(s):

Shawn D. Hingtgen ◽

Zhenbo Li ◽

William Kutschke ◽

Xin Tian ◽

Ram V. Sharma ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Viral Vectors ◽

Pressure Overload ◽

Dominant Negative ◽

Cardiomyocyte Hypertrophy ◽

Luciferase Expression ◽

Akt Activation ◽

Dominant Negative Form

Recent studies from our laboratory and others have shown that increases in cytoplasmic superoxide (O2·−) levels and Akt activation play a key role in agonist-stimulated NF-κB activation and cardiomyocyte hypertrophy in vitro. In this study, we tested the hypothesis that adenovirus (Ad)-mediated intramyocardial gene transfer of cytoplasmic superoxide dismutase (AdCu/ZnSOD) or a dominant-negative form of Akt (AdDNAkt) in mice would attenuate pressure overload-induced increases in activation of the redox-sensitive transcription factor NF-κB and cardiac hypertrophy. Adult C57BL/6 mice were subjected to thoracic aortic banding (TAB) or sham surgery, and intramyocardial injections of viral vectors (AdCu/ZnSOD, AdDNAkt, or control) were performed. There was robust transgene expression in the heart, which peaked 6–7 days after injection and then declined to undetectable levels by 12–14 days. In mice injected with AdBgL II, TAB caused a significant increase in O2·− generation and cardiac mass at 1 wk, and these responses were markedly attenuated by AdCu/ZnSOD. In addition, TAB induced time-dependent activation of NF-κB in the myocardium as measured longitudinally by in vivo bioluminescent imaging of NF-κB-dependent luciferase expression. This was also abolished by intracardiac AdCu/ZnSOD or AdDNAkt, but not the control vector. The inhibition of Akt and O2·−-mediated NF-κB activation in TAB hearts was associated with an attenuation of cardiac hypertrophy. Since a direct cause-and-effect relationship between NF-κB activation and cardiomyocyte hypertrophy has been established previously, our data support the hypothesis that increased O2·− generation and Akt activation are key signaling intermediates in pressure overload-induced activation of NF-κB and cardiac hypertrophy.

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Baicalin Attenuates Cardiac Dysfunction and Myocardial Remodeling in a Chronic Pressure-Overload Mice Model

Cellular Physiology and Biochemistry ◽

10.1159/000459708 ◽

2017 ◽

Vol 41 (3) ◽

pp. 849-864 ◽

Cited By ~ 19

Author(s):

Yanqing Zhang ◽

Pingping Liao ◽

Meng’en Zhu ◽

Wei Li ◽

Dan Hu ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Cardiac Dysfunction ◽

Cardiac Fibrosis ◽

Ventricular Remodeling ◽

Pressure Overload ◽

Protective Effects ◽

Mice Model ◽

Ischaemic Injury

Background/Aims: Baicalin has been shown to be effective for various animal models of cardiovascular diseases, such as pulmonary hypertension, atherosclerosis and myocardial ischaemic injury. However, whether baicalin plays a role in cardiac hypertrophy remains unknown. Here we investigated the protective effects of baicalin on cardiac hypertrophy induced by pressure overload and explored the potential mechanisms involved. Methods: C57BL/6J-mice were treated with baicalin or vehicle following transverse aortic constriction or Sham surgery for up to 8 weeks, and at different time points, cardiac function and heart size measurement and histological and biochemical examination were performed. Results: Mice under pressure overload exhibited cardiac dysfunction, high mortality, myocardial hypertrophy, increased apoptosis and fibrosis markers, and suppressed cardiac expression of PPARα and PPARβ/δ. However, oral administration of baicalin improved cardiac dysfunction, decreased mortality, and attenuated histological and biochemical changes described above. These protective effects of baicalin were associated with reduced heart and cardiomyocyte size, lower fetal genes expression, attenuated cardiac fibrosis, lower expression of profibrotic markers, and decreased apoptosis signals in heart tissue. Moreover, we found that baicalin induced PPARα and PPARβ/δ expression in vivo and in vitro. Subsequent experiments demonstrated that long-term baicalin treatment presented no obvious cardiac lipotoxicity. Conclusions: The present results demonstrated that baicalin attenuates pressure overload induced cardiac dysfunction and ventricular remodeling, which would be due to suppressed cardiac hypertrophy, fibrosis, apoptosis and metabolic abnormality.

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Abstract 342: Upregulation Of Mir-21 During Cardiac Hypertrophy Induces Down-regulation Of An Inhibitor Of The Ras-MAPK Pathway, Sprouty 2

Circulation ◽

10.1161/circ.116.suppl_16.ii_51 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Danish Sayed ◽

Minzhen He ◽

Leng-Yi Chen ◽

Jacqueline Lypowy ◽

Maha Abdellatif

Keyword(s):

Cardiac Hypertrophy ◽

Ventricular Remodeling ◽

Mapk Pathway ◽

Pressure Overload ◽

Mapk Signaling ◽

Compensatory Hypertrophy ◽

Immunocytochemical Staining ◽

Down Regulation ◽

Mrna Targets ◽

Enhanced Expression

MicroRNA (miRNA) are ~22 ribonucleotides-long, with a potential to recognize multiple mRNA targets guided by sequence complimentarity. This class of molecules is functionally versatile, with the capacity to specifically inhibit translation, as well as, induce mRNA degradation, through targeting the 3′ untranslated regions. The levels of individual miRNA vary under different developmental, biological, or pathological conditions, thus, implicating them in normal and pathological cellular attributes. We have previously reported a miRNA signature that distinguishes pressure-overload compensatory hypertrophy by recapitulating the neonatal pattern. In that model we found that miR-21 is one of the highest differentially expressed miRNA (~8x). Thus, we hypothesized that miR-21 may contribute to the development of hypertrophy by inducing down-regulation of antagonizing genes. To experimentally test the effect of miR-21 on cardiac myocytes, we generated adenoviruses harboring primary miR-21 or, uniquely, anti-miR-21 sequences. These viruses were used to infect cultured myocytes. Interestingly, overexpression of miR-21 resulted in extensive, dose-dependent, branching (sprouting) of the cells. Computational predictions by ’TargetScanS’ identified Sprouty 1 and 2 as potential targets. Subsequently, we confirmed down-regulation of sprouty by over-expression of miR-21. Conversely, knocking down miR-21, using anti-miR-21, resulted in enhanced expression of sprouty during growth-induced conditions. Immunocytochemical staining shows that it is localized to sarcomeric structures and the nucleus. Sprouty is a known inhibitor of the Ras-MAPK signaling pathway and is, concordantly, downregulated in many forms of cancer. Notably, sprouty also negatively regulates ureteric and tracheal branching during morphogenesis. In heart, sprouty has been suggested to control myocyte size and vascularization during mechanical stress-induced ventricular remodeling. Thus, we propose that upregulation of miR-21 during cardiac hypertrophy, induces down-regulation of sprouty, which results in activation of the Ras-MAPK pathway. Moreover, down-regulation of sprouty is necessary for the increased myocyte branching observed during hypertrophy.

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Pinoresinol diglucoside (PDG) attenuates cardiac hypertrophy via AKT/mTOR/NF-κB signaling in pressure overload-induced rats

Journal of Ethnopharmacology ◽

10.1016/j.jep.2021.113920 ◽

2021 ◽

Vol 272 ◽

pp. 113920

Author(s):

Yusha Chen ◽

Ruiyan Pan ◽

Juanjuan Zhang ◽

Tianming Liang ◽

Juan Guo ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Pressure Overload ◽

Pinoresinol Diglucoside

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Dietary Capsaicin Ameliorates Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis Through the Transient Receptor Potential Vanilloid Type 1

American Journal of Hypertension ◽

10.1093/ajh/hpu068 ◽

2014 ◽

Vol 27 (12) ◽

pp. 1521-1529 ◽

Cited By ~ 22

Author(s):

Q. Wang ◽

S. Ma ◽

D. Li ◽

Y. Zhang ◽

B. Tang ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Transient Receptor Potential ◽

Pressure Overload ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Transient Receptor

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Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽

10.3390/antiox10060931 ◽

2021 ◽

Vol 10 (6) ◽

pp. 931

Author(s):

Anureet K. Shah ◽

Sukhwinder K. Bhullar ◽

Vijayan Elimban ◽

Naranjan S. Dhalla

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Cardiac Remodeling ◽

Cardiac Dysfunction ◽

Critical Role ◽

Pressure Overload ◽

Hypertrophied Heart ◽

Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

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