Isolevuglandin scavenger attenuates pressure overload-induced cardiac oxidative stress, cardiac hypertrophy, heart failure and lung remodeling

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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LCZ696 Ameliorates Oxidative Stress and Pressure Overload-Induced Pathological Cardiac Remodeling by Regulating the Sirt3/MnSOD Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/9815039 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Shi Peng ◽

Xiao-feng Lu ◽

Yi-ding Qi ◽

Jing Li ◽

Juan Xu ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Cardiac Hypertrophy ◽

Pressure Overload ◽

Neonatal Rat ◽

Cardiomyocyte Hypertrophy ◽

Rat Cardiomyocytes ◽

Pathological Cardiac Hypertrophy

Aims. We aimed to investigate whether LCZ696 protects against pathological cardiac hypertrophy by regulating the Sirt3/MnSOD pathway. Methods. In vivo, we established a transverse aortic constriction animal model to establish pressure overload-induced heart failure. Subsequently, the mice were given LCZ696 by oral gavage for 4 weeks. After that, the mice underwent transthoracic echocardiography before they were sacrificed. In vitro, we introduced phenylephrine to prime neonatal rat cardiomyocytes and small-interfering RNA to knock down Sirt3 expression. Results. Pathological hypertrophic stimuli caused cardiac hypertrophy and fibrosis and reduced the expression levels of Sirt3 and MnSOD. LCZ696 alleviated the accumulation of oxidative reactive oxygen species (ROS) and cardiomyocyte apoptosis. Furthermore, Sirt3 deficiency abolished the protective effect of LCZ696 on cardiomyocyte hypertrophy, indicating that LCZ696 induced the upregulation of MnSOD and phosphorylation of AMPK through a Sirt3-dependent pathway. Conclusions. LCZ696 may mitigate myocardium oxidative stress and apoptosis in pressure overload-induced heart failure by regulating the Sirt3/MnSOD pathway.

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Plin5 deficiency exacerbates pressure overload-induced cardiac hypertrophy and heart failure by enhancing myocardial fatty acid oxidation and oxidative stress

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2019.07.006 ◽

2019 ◽

Vol 141 ◽

pp. 372-382 ◽

Cited By ~ 5

Author(s):

Chao Wang ◽

Yuan Yuan ◽

Jie Wu ◽

Yuanlin Zhao ◽

Xing Gao ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Fatty Acid ◽

Cardiac Hypertrophy ◽

Fatty Acid Oxidation ◽

Pressure Overload ◽

Acid Oxidation ◽

Myocardial Fatty Acid ◽

And Oxidative Stress

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Abstract 350: Atorvastatin Attenuates Pressure Overload-induced Cardiac Hypertrophy and Dysfunction Through Enhanced Autophagy

Circulation Research ◽

10.1161/res.117.suppl_1.350 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Zhuo Zhao ◽

Wei Wang ◽

Hua-Ting Wang ◽

Qing-Xin Geng ◽

Di Zhao ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Western Blot ◽

Mrna Level ◽

Mammalian Target Of Rapamycin ◽

Pressure Overload ◽

Oral Gavage ◽

Atorvastatin Treatment ◽

Developing Heart ◽

Phosphorylated Akt

Aims: Cardiac hypertrophy is a maladaptive change in response to pressure overload and is also an important risk for developing heart failure. We previously demonstrated that atorvastatin inhibits cardiac hypertrophy and remodeling in a mouse model of transverse aorta constriction (TAC). This study was designed to determine the regulation of atorvastatin on cardiac autophagy and its association with the development of cardiac hypertrophy and dysfunction in the mice TAC model. Methods and results: TAC or sham operations were performed in male C57/L6 mice at 8 weeks of age. Atorvastatin (50 mg/kg/day) or vehicle (normal saline) were administered daily by oral gavage to TAC mice (n=10 per group). Echocardiography and real-time PCR data showed that chronic atorvastatin treatment for four weeks significantly attenuated pressure overload-induced cardiac hypertrophy and dysfunction, as well as cardiac mRNA level of atrial natriuretic factor (ANF), a biomarker of cardiac hypertrophy and heart failure. After 4 weeks of TAC, results from electron microscopy and Western blot showed that cardiac autophagy was activated, evidenced by the increased expression of microtubule-associated protein-1 light chain 3-II (LC3-II), Beclin-1, caspase-3, and the formation of autophagosomes. Interestingly, cardiac autophagy was further increased by the treatment of atorvastatin for 4 weeks. Western blot analysis showed phosphorylated Akt and mammalian target of rapamycin (p-mTor) decreased in the heart of TAC versus sham mice, which were further decreased by atorvastatin treatment. Conclusions: These findings suggest that atorvastatin attenuates cardiac hypertrophy and dysfunction in TAC mice probably through its regulation on cardiac autophagy via Akt/mTor pathways.

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A gene therapeutic approach to inhibit calcium and integrin binding protein 1 ameliorates maladaptive remodelling in pressure overload

Cardiovascular Research ◽

10.1093/cvr/cvy154 ◽

2018 ◽

Vol 115 (1) ◽

pp. 71-82 ◽

Cited By ~ 5

Author(s):

Andrea Grund ◽

Malgorzata Szaroszyk ◽

Janina K Döppner ◽

Mona Malek Mohammadi ◽

Badder Kattih ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Cardiac Function ◽

Binding Protein ◽

Treatment Strategies ◽

Pressure Overload ◽

Cellular Growth ◽

Neonatal Rat ◽

Rat Cardiomyocytes ◽

Pathological Cardiac Hypertrophy

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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P66Shc Deletion Ameliorates Oxidative Stress and Cardiac Dysfunction in Pressure Overload-Induced Heart Failure

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2019.09.003 ◽

2020 ◽

Vol 26 (3) ◽

pp. 243-253 ◽

Cited By ~ 1

Author(s):

YONG Wang ◽

HUA Qu ◽

JING Liu

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Cardiac Dysfunction ◽

Pressure Overload

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Cacao Bean Polyphenols Inhibit Cardiac Hypertrophy and Systolic Dysfunction in Pressure Overload-induced Heart Failure Model Mice

Planta Medica ◽

10.1055/a-1191-7970 ◽

2020 ◽

Vol 86 (17) ◽

pp. 1304-1312

Author(s):

Nurmila Sari ◽

Yasufumi Katanasaka ◽

Hiroki Honda ◽

Yusuke Miyazaki ◽

Yoichi Sunagawa ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Gene Transcription ◽

Binding Protein ◽

Systolic Dysfunction ◽

Pressure Overload ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal

AbstractPathological stresses such as pressure overload and myocardial infarction induce cardiac hypertrophy, which increases the risk of heart failure. Cacao bean polyphenols have recently gained considerable attention for their beneficial effects on cardiovascular diseases. This study investigated the effect of cacao bean polyphenols on the development of cardiac hypertrophy and heart failure. Cardiomyocytes from neonatal rats were pre-treated with cacao bean polyphenols and then stimulated with 30 µM phenylephrine. C57BL/6j male mice were subjected to sham or transverse aortic constriction surgery and then orally administered with vehicle or cacao bean polyphenols. Cardiac hypertrophy and function were examined by echocardiography. In cardiomyocytes, cacao bean polyphenols significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy and hypertrophic gene transcription. Extracellular signal-regulated kinase 1/2 and GATA binding protein 4 phosphorylation induced by phenylephrine was inhibited by cacao bean polyphenols treatment in the cardiomyocytes. Cacao bean polyphenols treatment at 1200 mg/kg significantly ameliorated left ventricular posterior wall thickness, fractional shortening, hypertrophic gene transcription, cardiac hypertrophy, cardiac fibrosis, and extracellular signal-regulated kinase 1/2 phosphorylation induced by pressure overload. In conclusion, these findings suggest that cacao bean polyphenols prevent pressure overload-induced cardiac hypertrophy and systolic dysfunction by inhibiting the extracellular signal-regulated kinase 1/2-GATA binding protein 4 pathway in cardiomyocytes. Thus, cacao bean polyphenols may be useful for heart failure therapy in humans.

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Cytosolic H2O2 mediates hypertrophy, apoptosis, and decreased SERCA activity in mice with chronic hemodynamic overload

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00084.2014 ◽

2014 ◽

Vol 306 (10) ◽

pp. H1453-H1463 ◽

Cited By ~ 32

Author(s):

Fuzhong Qin ◽

Deborah A. Siwik ◽

David R. Pimentel ◽

Robert J. Morgan ◽

Andreia Biolo ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Cardiac Myocyte ◽

Pressure Overload ◽

Left Ventricular ◽

Transgenic Expression ◽

Myocardial Oxidative Stress ◽

Plasmic Reticulum ◽

Oxidative Modifications ◽

Hemodynamic Overload

Oxidative stress in the myocardium plays an important role in the pathophysiology of hemodynamic overload. The mechanism by which reactive oxygen species (ROS) in the cardiac myocyte mediate myocardial failure in hemodynamic overload is not known. Accordingly, our goals were to test whether myocyte-specific overexpression of peroxisomal catalase (pCAT) that localizes in the sarcoplasm protects mice from hemodynamic overload-induced failure and prevents oxidation and inhibition of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), an important sarcoplasmic protein. Chronic hemodynamic overload was caused by ascending aortic constriction (AAC) for 12 wk in mice with myocyte-specific transgenic expression of pCAT. AAC caused left ventricular hypertrophy and failure associated with a generalized increase in myocardial oxidative stress and specific oxidative modifications of SERCA at cysteine 674 and tyrosine 294/5. pCAT overexpression ameliorated myocardial hypertrophy and apoptosis, decreased pathological remodeling, and prevented the progression to heart failure. Likewise, pCAT prevented oxidative modifications of SERCA and increased SERCA activity without changing SERCA expression. Thus cardiac myocyte-restricted expression of pCAT effectively ameliorated the structural and functional consequences of chronic hemodynamic overload and increased SERCA activity via a post-translational mechanism, most likely by decreasing inhibitory oxidative modifications. In pressure overload-induced heart failure cardiac myocyte cytosolic ROS play a pivotal role in mediating key pathophysiologic events including hypertrophy, apoptosis, and decreased SERCA activity.

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Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1721298115 ◽

2018 ◽

Vol 115 (30) ◽

pp. E7129-E7138 ◽

Cited By ~ 31

Author(s):

Shinichiro Sunamura ◽

Kimio Satoh ◽

Ryo Kurosawa ◽

Tomohiro Ohtsuki ◽

Nobuhiro Kikuchi ◽

...

Keyword(s):

Oxidative Stress ◽

Pulmonary Hypertension ◽

Cardiac Hypertrophy ◽

Cardiac Dysfunction ◽

High Throughput Screening ◽

Histological Analysis ◽

Rho Kinase ◽

Pressure Overload ◽

Aortic Constriction ◽

Patients With Heart Failure

Although postcapillary pulmonary hypertension (PH) is an important prognostic factor for patients with heart failure (HF), its pathogenesis remains to be fully elucidated. To elucidate the different roles of Rho-kinase isoforms, ROCK1 and ROCK2, in cardiomyocytes in response to chronic pressure overload, we performed transverse aortic constriction (TAC) in cardiac-specific ROCK1-deficient (cROCK1−/−) and ROCK2-deficient (cROCK2−/−) mice. Cardiomyocyte-specific ROCK1 deficiency promoted pressure-overload-induced cardiac dysfunction and postcapillary PH, whereas cardiomyocyte-specific ROCK2 deficiency showed opposite results. Histological analysis showed that pressure-overload-induced cardiac hypertrophy and fibrosis were enhanced in cROCK1−/− mice compared with controls, whereas cardiac hypertrophy was attenuated in cROCK2−/− mice after TAC. Consistently, the levels of oxidative stress were up-regulated in cROCK1−/− hearts and down-regulated in cROCK2−/− hearts compared with controls after TAC. Furthermore, cyclophilin A (CyPA) and basigin (Bsg), both of which augment oxidative stress, enhanced cardiac dysfunction and postcapillary PH in cROCK1−/− mice, whereas their expressions were significantly lower in cROCK2−/− mice. In clinical studies, plasma levels of CyPA were significantly increased in HF patients and were higher in patients with postcapillary PH compared with those without it. Finally, high-throughput screening demonstrated that celastrol, an antioxidant and antiinflammatory agent, reduced the expressions of CyPA and Bsg in the heart and the lung, ameliorating cardiac dysfunction and postcapillary PH induced by TAC. Thus, by differentially affecting CyPA and Bsg expressions, ROCK1 protects and ROCK2 jeopardizes the heart from pressure-overload HF with postcapillary PH, for which celastrol may be a promising agent.

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