scholarly journals MicroRNAs in Cardiac Hypertrophy

2019 ◽  
Vol 20 (19) ◽  
pp. 4714 ◽  
Author(s):  
Nadine Wehbe ◽  
Suzanne Nasser ◽  
Gianfranco Pintus ◽  
Adnan Badran ◽  
Ali Eid ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Output ◽  
Cardiac Hypertrophy ◽  
Signaling Pathways ◽  
Cardiac Remodeling ◽  
Pathological Conditions ◽  
Recent Advances ◽  
Short Period

Like other organs, the heart undergoes normal adaptive remodeling, such as cardiac hypertrophy, with age. This remodeling, however, is intensified under stress and pathological conditions. Cardiac remodeling could be beneficial for a short period of time, to maintain a normal cardiac output in times of need; however, chronic cardiac hypertrophy may lead to heart failure and death. MicroRNAs (miRNAs) are known to have a role in the regulation of cardiac hypertrophy. This paper reviews recent advances in the field of miRNAs and cardiac hypertrophy, highlighting the latest findings for targeted genes and involved signaling pathways. By targeting pro-hypertrophic genes and signaling pathways, some of these miRNAs alleviate cardiac hypertrophy, while others enhance it. Therefore, miRNAs represent very promising potential pharmacotherapeutic targets for the management and treatment of cardiac hypertrophy.

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

Antioxidants ◽  
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.

Abstract P394: Angiotensin-(1-7) Attenuates Diastolic Dysfunction And Cardiac Remodeling In Murine Model Of Heart Failure With Preserved Ejection Fraction

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Pariya Edalat ◽  
Karina Gomes ◽  
Noura N Ballasy ◽  
Anshul S Jadli ◽  
Darrell D Belke ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Hypertrophy ◽  
Diastolic Dysfunction ◽  
Murine Model ◽  
Cardiac Remodeling ◽  
Control Group ◽  
Chow Diet ◽  
Preserved Ejection Fraction ◽  
Phosphorylation Level

Background: Heart failure with preserved ejection fraction (HFpEF) is a global public health epidemic that accounts for half of the heart failure cases. Various therapeutic approaches have been tested to block the activation of the Renin-Angiotensin System (RAS), including AT1R blockers (ARBs), Angiotensin-Converting Enzyme (ACE) inhibitors (ACEi), and direct renin inhibitors (DRIs) with modest to negligible benefits. The discovery of ACE2, a novel homolog of ACE, has advanced our understanding of the RAS. ACE2 is a monocarboxypeptidase that degrades Ang II into Ang-(1-7), which works via the activation of the Mas receptor. It has been well understood that the actions of Ang-(1-7) attenuate cardiac remodeling, production of ROS, and cardiac fibrosis. Objective: To determine the therapeutic role of Ang-(1-7) in HFpEF and identify the molecular mechanism related to its action. Methods and Results: To generate a murine model of HFpEF, male WT mice (n=24) were subjected to HFD in addition to eNOS inhibition with L-NAME (0.5 g l-1 in drinking water), as previously described. The control group (n=12) received chow diet and normal tap water. The murine model of HFpEF was validated using the non-invasive transthoracic echocardiography and invasive pressure-volume (PV) loop analyses, which exhibited diastolic dysfunction as well as cardiac hypertrophy. To evaluate the effects of Ang-(1-7) on HFpEF, animals were administered with either saline (n=12) or Ang-(1-7) (n=12) (24 μg/kg/day) for four weeks. Ang-(1-7) treatment improved diastolic function by reducing LVEDP (Ctrl: 8.267±1.254; HFD+L-NAME: 17.64±1.925; Ang-(1-7): 9.100±1.578) and Tau value (Ctrl: 7.365±0.5752; HFD+L-NAME: 9.224±0.3569; Ang-(1-7): 7.381±0.3041). Furthermore, Ang-(1-7) reduced cardiac hypertrophy by reducing the phosphorylation level of MAPK ERK 1/2 (Ctrl: 0.9074±0.1088; HFD+L-NAME: 1.212±0.1369; Ang-(1-7): 0.5615±0.1502) and increasing the phosphorylation level of AMPK (Ctrl: 0.1502±0.1502; HFD+L-NAME: 0.6127±0.06414; Ang-(1-7): 0.7852±0.1006). Ang-(1-7) treatment also reduces cardiomyocytes’ size and decreases interstitial fibrosis, as indicated by WGA and PSR staining. Conclusion: Ang-(1-7) treatment attenuated the development of HFD+L-NAME-induced HFpEF, reduced cardiac hypertrophy, and improved metabolic function.

scholarly journals Qiliqiangxin Attenuates Cardiac Remodeling via Inhibition of TGF-β1/Smad3 and NF-κB Signaling Pathways in a Rat Model of Myocardial Infarction

2018 ◽  
Vol 45 (5) ◽  
pp. 1797-1806 ◽  
Author(s):  
Anbang Han ◽  
Yingdong Lu ◽  
Qi Zheng ◽  
Jian Zhang ◽  
YiZhou Zhao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Signaling Pathways ◽  
Rat Model ◽  
Cardiac Remodeling ◽  
Left Ventricular ◽  
Protective Effects ◽  
Tnf Α ◽  
Tgf Β1

Background/Aims: Qiliqiangxin (QL), a traditional Chinese medicine, has been demonstrated to be effective and safe for the treatment of chronic heart failure. Left ventricular (LV) remodeling causes depressed cardiac performance and is an independent determinant of morbidity and mortality after myocardial infarction (MI). Our previous studies have shown that QL exhibits cardiac protective effects against heart failure after MI. The objective of this study was to explore the effects of QL on myocardial fibrosis in rats with MI and to investigate the underlying mechanism of these effects. Methods: A rat model of acute myocardial infarction was induced by ligating the left anterior descending coronary artery. The rats were treated with QL (1.0 g/kg/day) for 4 weeks after surgery. Echocardiography and histology examination were performed to evaluate heart function and fibrosis, respectively. Protein levels of transforming growth factor-β1 (TGF-β1), phosphorylated Smad3 (p-Smad3), phosphorylated Smad7 (p-Smad7), collagen I (Col- I), alpha smooth muscle actin (a-SMA), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), nuclear factor κB (NF-κB), and phosphorylated inhibitor of kappa B alpha (p-IκBα) were measured by western blot analysis. Results: QL treatment ameliorated adverse cardiac remodeling 8 weeks after AMI, including better preservation of cardiac function, decreased inflammation, and reduced fibrosis. In addition, QL treatment reduced Col-I, a-SMA, TGF-β1, and p-Smad3 expression levels but increased p-Smad7 levels in postmyocardial infarct rat hearts. QL administration also reduced the elevated levels of cardiac inflammation mediators, such as TNF-α and IL-6, as well as NF-κB and p-IκBα expression. Conclusions: QL therapy exerted protective effects against cardiac remodeling potentially by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways, thereby preserving cardiac function, as well as reducing myocardial inflammation and fibrosis.

scholarly journals AngiotensinII Preconditioning Promotes AngiogenesisIn Vitrovia ERKs Phosphorylation

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Aili Guan ◽  
Yunzeng Zou ◽  
Hui Gong ◽  
Yuhong Niu ◽  
Yong Ye ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cardiac Hypertrophy ◽  
Protein Kinases ◽  
Cardiac Remodeling ◽  
Microvascular Endothelial Cells ◽  
Long Period ◽  
Extracellular Signal ◽  
Short Period ◽  
Microvascular Endothelial ◽  
Cardiac Microvascular Endothelial Cells

AngiotensinII (AngII) is involved in not only the formation of cardiac hypertrophy but also the development of cardiac remodeling both of which are associated with myocardial angiogenesis. This study was therefore performed to clarify the effects of AngII on the formation of vasculatures by cultured cardiac microvascular endothelial cells (CMVECs) after a long-period stimulation with or without the AngII preconditioning. Incubation with AngII for 18 hrs significantly impaired the formation of capillary-like tubes comparing to that without AngII. CMVECs with AngII pretreatment for 5 and 10 min formed more capillary-like tubes than those without AngII pretreatment, suggesting that preconditioning with AngII at a lower dose for a short period could prevent the further damage of CMVECs by a higher concentration of AngII. Moreover, AngII (10-7 M) stimulation for 5 and 10 min significantly induced the increase in extracellular signal-regulated protein kinases (ERKs) phosphorylation, and an ERKs inhibitor, PD98059, abrogated the increase in the formation of capillary-like tubes induced by the AngII-pretreatment. In conclusion, preconditioning with a lower concentration of AngII for a short period prevents the subsequent impairment of CMVECs by a higher dose of AngII, at least in part, through the increase in ERKs phosphorylation.

scholarly journals Autophagy modulation: a potential therapeutic approach in cardiac hypertrophy

2017 ◽  
Vol 313 (2) ◽  
pp. H304-H319 ◽  
Author(s):  
Xuejun Wang ◽  
Taixing Cui
Keyword(s):  
Heart Failure ◽  
Quality Control ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Energy Crisis ◽  
Pathogenic Role ◽  
Evolutionarily Conserved ◽  
Control Survival

Autophagy is an evolutionarily conserved process used by the cell to degrade cytoplasmic contents for quality control, survival for temporal energy crisis, and catabolism and recycling. Rapidly increasing evidence has revealed an important pathogenic role of altered activity of the autophagosome-lysosome pathway (ALP) in cardiac hypertrophy and heart failure. Although an early study suggested that cardiac autophagy is increased and that this increase is maladaptive to the heart subject to pressure overload, more recent reports have overwhelmingly supported that myocardial ALP insufficiency results from chronic pressure overload and contributes to maladaptive cardiac remodeling and heart failure. This review examines multiple lines of preclinical evidence derived from recent studies regarding the role of autophagic dysfunction in pressure-overloaded hearts, attempts to reconcile the discrepancies, and proposes that resuming or improving ALP flux through coordinated enhancement of both the formation and the removal of autophagosomes would benefit the treatment of cardiac hypertrophy and heart failure resulting from chronic pressure overload.

Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets

2015 ◽  
Vol 89 (9) ◽  
pp. 1401-1438 ◽  
Author(s):  
Yow Keat Tham ◽  
Bianca C. Bernardo ◽  
Jenny Y. Y. Ooi ◽  
Kate L. Weeks ◽  
Julie R. McMullen
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Signaling Pathways ◽  
Therapeutic Targets ◽  
Novel Therapeutic

Myofibroblast Deficiency of LSD1 Alleviates TAC-Induced Heart Failure

2021 ◽  
Author(s):  
Jin-Ling Huo ◽  
Lemin Jiao ◽  
Qi An ◽  
Xiuying Chen ◽  
Yuruo Qi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Transforming Growth Factor ◽  
Heart Function ◽  
Wild Type Mouse ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Ang Ii

Rationale: Histone lysine specific demethylase 1 (LSD1) is an important epigenetic anti-tumor drug target, whose inhibitors are currently in phase Ⅰ/Ⅱ clinical trials. However, the potential side effects of LSD1 inhibition in the progress of cardiac remodeling to heart failure remain to be investigated. Objective: To evaluate the roles of myofibroblast- or cardiomyocyte-specific LSD1 deficiency in pressure overload-induced cardiac remodeling. Methods and Results: Adult mouse cardiac fibroblasts (CFs)，neonatal rat cardiac myocytes (NRCMs) and fibroblasts (NRCFs) were isolated, respectively. The myofibroblast-specific and cardiomyocyte-specific LSD1 inducible knockout mice were then generated. We found that LSD1 was increased not only in human DCM (dilated cardiomyopathy) hearts, but also in wild type mouse heart homogenates and isolated CFs, following 20 weeks of transverse aortic constriction (TAC). The upregulation of LSD1 was also observed in Ang II-treated NRCFs, which was reversed by LSD1 silence or its activity inhibition by ORY-1001. These findings suggested a potential involvement of LSD1 in cardiac remodeling. Importantly, myofibroblast-specific LSD1 inducible knockout in vivo significantly alleviated systolic dysfunction, cardiac hypertrophy and fibrosis, following 6 and 20 weeks of TAC. Mechanistically, through RNA-sequencing and the following western blot analysis, we found that loss of LSD1 in Ang II-induced myofibroblasts not only inhibited the intracellular upregulation of transforming growth factor β1 (TGFβ1), its downstream effectors Smad2/3 phosphorylation, as well as the phosphorylation of p38, ERK1/2 and JNK, but also reduced the supernatant TGFβ1 secretion, which then decreased myocyte hypertrophy in the indirect co-culture model. On the other hand, cardiomyocyte-specific LSD1 inducible knockout in vivo triggered the reprogramming of fetal genes, mild cardiac hypertrophy and dysfunction under both basal and stressed conditions. Conclusions: Our findings, for the first time, implicate that myofibroblast-specific LSD1 deletion attenuates TAC-induced cardiac remodeling and improves heart function, suggesting that LSD1 is a potential therapeutic target for late stage heart failure.

scholarly journals Differential Regulation of ERK and mTOR Signaling Pathways in Failing Human Hearts

2020 ◽  
Author(s):  
Rebecca Autenried ◽  
Eric T. Weatherford ◽  
Yuan Zhang ◽  
Helena C. Kenny ◽  
Renata O. Pereira ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Signaling Pathways ◽  
Insulin Signaling ◽  
Human Heart ◽  
Ventricular Remodeling ◽  
Mtor Signaling ◽  
Heart Failure Patients ◽  
Healthy Donors ◽  
End Stage

STUCTURED ABSTRACTObjectivesWe hypothesized that disruption of pathways downstream of insulin signaling characterize pathological ventricular remodeling and may provide insights into the pathophysiology of heart failure. To test this hypothesis, we examined components of the insulin signaling pathway in tissue explants from human hearts obtained from healthy donors and explants from heart failure patients with and without diabetes, receiving a heart transplant.BackgroundPathologic ventricular remodeling accompanied by hypertrophic growth is a common characteristic of heart failure including in patients with diabetes. The contribution of aberrant insulin signaling in the pathophysiology of diabetes-associated heart failure and, ventricular hypertrophy is incompletely understood.MethodsHearts of twenty non-failing donor participants and thirty-one human cardiac transplant patients were assessed for insulin signaling. Samples were sorted into four groups: non-failing non-obese (NFN), non-failing obese (NFO), failing non-diabetic (FND), and failing diabetic (FDM). Ejection fraction was assessed by echocardiography and clinically relevant systolic dysfunction was defined as left ventricular ejection fraction <50%. A clinical diabetes diagnosis was obtained from chart review. As a proxy measure of prolonged glycemia, plasma fructosamine was determined by colorimetric assay. Insulin signaling, protein phosphorylation, and total protein levels were measured by immunoblot.ResultsWhen all groups were analyzed together, hyperglycemia correlated with increased cardiac size and decreased function. Cardiac size correlated with increased levels of insulin receptor (IRb) and phosphorylated ERK but with decreased levels of phosphorylated Akt and mTOR. IRb and p-Akt correlated with fructosamine, but p-ERK and p-mTOR did not. Cardiac hypertrophy correlated with decreased GLUT1 levels, increased Hexokinase I and repression mitochondrial complexes I, III and IV in concert with activation of AMPK.ConclusionsAltered insulin signaling, characterized by increased IRb content, activation of ERK but repression of Akt and mTOR signaling pathways is present in the end-stage failing human heart. Similar divergence of insulin signaling pathways have been previously described in vascular smooth muscle.CONDENSED ABSTRACTWe hypothesized that disruption of pathways downstream of insulin signaling characterize pathological ventricular remodeling and may provide insights into pathophysiology. To test this hypothesis, we examined components of the insulin signaling pathway in tissue explants from human hearts obtained from healthy donors and explants from heart failure patients with and without diabetes, receiving a heart transplant. We found that altered insulin signaling, characterized by increased IRb content and activation of ERK but repression of Akt and mTOR signaling pathways is present in the end-stage failing human heart.HIGHLIGHTSIn this cross-sectional analysis of end-stage failing human cardiac tissue, hyperglycemia correlated with cardiac dysfunction and increased cardiac hypertrophy.While myocardial insulin resistance may exist in the PI3K-Akt-mTOR pathway in end-stage failing human hearts, ERK signaling is induced, which may contribute to cardiac hypertrophy in a manner that is independent of plasma insulin.Differential activation of branches of insulin signaling in human failing hearts, supports the concept of selective insulin resistance.These findings have implications for the consequences of modulating systemic insulin sensitivity in patients with heart failure.

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