The Role of Cardiac Remodeling in the Progression of Heart Failure Disease

Background: Hepatokine selenoprotein P (SeP) contributes to insulin resistance and hyperglycemia in patients with type 2 diabetes. Although clinical studies suggest the insulin resistance is an independent risk factor of heart failure and inhibition of SeP protects the heart from ischemia reperfusion injury, the role of SeP in pathogenesis of chronic heart failure is not well understood. Objective: We examined the role of SeP in the regulation of cardiac remodeling in response to pressure overload. Methods and Results: We measured serum SeP levels in 22 patients for heart failure with reduced ejection fraction (HFrEF; LVEF<50%) and 22 normal subjects. Serum levels of SeP were significantly elevated in patients with HFrEF compared to in normal subjects (3.55 ± 0.43 vs 2.98 ± 0.43, p<0.01). To examine the role of SeP in cardiac remodeling, SeP knockout (KO) and wild-type (WT) mice were subjected to pressure overload (transverse aortic constriction (TAC)) for 2 weeks. The mortality rate following TAC was significantly decreased in SeP KO mice compared to WT mice (22.5 % in KO mice (n=40) vs 52.3 % in WT mice (n=39) p<0.01). LV weight/tibial length (TL) was significantly smaller in SeP KO mice than in WT mice (6.75 ± 0.24 vs 8.33 ± 0.32, p<0.01). Lung weight/TL was significantly smaller in SeP KO than in WT mice (10.46 ± 0.44 vs 16.38 ± 1.12, p<0.05). Interestingly, hepatic expression of SeP in WT was significantly increased by TAC. To determine whether hepatic overexpression of SeP affects TAC-induced cardiac hypertrophy, a hydrodynamic injection method was used to generate mice that overexpress SeP mRNA in the liver. Hepatic overexpression of SeP in SeP KO mice lead to a significant increase in LV weight/TL and Lung weight/TL after TAC compared to that in other SeP KO mice. Conclusions: These results suggest that serum levels of SeP were elevated in patients with heart failure with reduced ejection fraction and cardiac pressure overload induced hepatic expression of SeP in mice model. Gene deletion of SeP attenuated cardiac hypertrophy and dysfunction in response to pressure overload in mice. SeP possibly plays a pivotal role in promoting cardiac remodeling through the liver-heart axis.

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The Emerging Role of MicroRNAs in Cardiac Remodeling and Heart Failure

Circulation Research ◽

10.1161/circresaha.108.183087 ◽

2008 ◽

Vol 103 (10) ◽

pp. 1072-1083 ◽

Cited By ~ 173

Author(s):

Vijay Divakaran ◽

Douglas L. Mann

Keyword(s):

Heart Failure ◽

Cardiac Remodeling

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Abstract 1271: IKKβ/NF-κB Pathway Protects Hearts from Hemodynamic Stress Mediated through Regulating MnSOD Expression

Circulation ◽

10.1161/circ.116.suppl_16.ii_259-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Shungo Hikoso ◽

Kinya Otsu ◽

Osamu Yamaguchi ◽

Toshihiro Takeda ◽

Masayuki Taniike ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Cardiac Remodeling ◽

Weight Ratio ◽

Pressure Overload ◽

Left Ventricular ◽

Negative Regulator ◽

Iκb Kinase ◽

Jnk Activation

Objectives: We have previously reported that NF-κB contributes to GPCR agonist-induced hypertrophy in cultured cardiomyocytes. However, the in vivo role of this pathway in the pathogenesis of cardiac remodeling remains to be elucidated. Although IκB kinase β (IKKβ)/NF-κB pathway is a major negative regulator of cell death, it can sensitize cells to death-inducing stimuli in some instances, thus it can be either anti- or pro-apoptotic. In this study, we aimed to clarify the role of IKKβ/NF-κB signaling in cardiac remodeling using cardiac-specific IKKβ deficient mice. Methods and Results: We crossed mice bearing an IKK β flox allele with mice expressing the Cre recombinase under the control of the myosin light chain 2v promoter ( MLC2v-Cre +/− ) to generate IKK β flox/flox ; MLC2v-Cre +/− mice (conditional knockout:CKO). Then, CKO mice (n=14) and control littermates bearing IKK β flox/flox (CTRL, n=14) were subjected to pressure overload by means of transverse aortic constriction (TAC). EMSA analysis revealed NF-κB DNA binding activity after TAC had attenuated in CKO hearts. One week after TAC, echocardiography showed significantly lower left ventricular fractional shortening (26.9±2.7% vs. 41.4±0.9%, p<0.01), and higher left ventricular end-diastolic dimension (4.02±0.14 mm vs. 3.47±0.08 mm, p<0.01) and lung weight/body weight ratio (11.1±1.4 vs. 5.5±0.1, p<0.01) in CKO mice compared with CTRL mice, indicating the development of heart failure in CKO mice. Number of apoptotic cells had increased in CKO hearts after TAC, suggesting that the enhanced apoptosis is a cause for heart failure. The expression levels of MnSOD mRNA and protein after TAC, which is one of NF-κB target genes, were significantly lower in CKO than those in CTRL mice. As a consequence, oxidative stress and JNK activation in CKO hearts after TAC had significantly increased compared with those in CTRL heart, suggesting that increased oxidative stress and enhanced JNK activity resulted in cardiomyocyte apoptosis in CKO hearts. Conclusion: These results show that IKKβ/NF-κB pathway in cardiomyocyte plays a protective role mediated through attenuation of oxidative stress and JNK activation in response to pressure overload.

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Abstract 4831: The A2B Adenosine Receptor Contributes to Post-Infarction Heart Failure

Circulation ◽

10.1161/circ.118.suppl_18.s_946 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Jason E Maas ◽

Milka Koupenova ◽

Katya Ravid ◽

John A Auchampach

Keyword(s):

Heart Failure ◽

Coronary Artery ◽

Infarct Size ◽

Adenosine Receptor ◽

Cardiac Remodeling ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Receptor Subtypes ◽

Infarction Heart

Recent studies have been directed at understanding the role of the A 2B receptor in regulating cardioprotection, coronary blood flow, fibroblast function, and inflammation. Unlike the other adenosine receptor subtypes, the A 2B receptor is emerging as a promoter of inflammation in chronic diseases such as asthma and conditions associated with tissue fibrosis. In this study, we used A 2B receptor gene “knock-out” (A 2B −/− ) mice to test the role of the A 2B receptor in infarction-induced heart failure and cardiac remodeling. A 2B −/− mice or wild-type (WT) littermates were subjected to permanent ligation of the left coronary artery or sham surgery. Cardiac morphology and function were assessed at 4 and 8 weeks after surgery by echocardiography. At the end of the study, systemic arterial and left ventricular pressures were obtained, after which the hearts were removed and histologically assessed for infarct size and fibrosis. WT hearts experienced significant left ventricular dilation and reduced systolic (fractional area shortening, myocardial performance index, and +dP/dt max ) and diastolic (end-diastolic pressure [EDP] elevated from 3.2 ± 0.8 mmHg in sham mice to 8.8 ± 1.5 mmHg in infarcted mice and tau was prolonged from 11.6 ± 1.7 ms to 22.3 ± 2.0 ms) function at 8 weeks after coronary artery ligation. Compared to WT mice, there were no significant differences in measures of post-infarction systolic function in A 2B −/− mice. However, EDP and tau were significantly improved (2.5 ± 1.5 mmHg and 17 ± 1.4 ms, respectively) and were not worsened compared to sham-operated A 2B −/− mice (2.7 ± 2.1 mmHg and 14.5 ± 1.8 ms, respectively). Moreover, interstitial fibrosis was elevated in the non-infarcted myocardium of WT mice subjected to coronary ligation, but not in A 2B −/− mice. Importantly, infarct size (WT = 39 ± 2% of the left ventricle; A 2B −/− = 43 ± 3%) and systemic blood pressure were not significantly different between WT and A 2B −/− mice. The data suggest that absence of the A 2B receptor results in preservation of diastolic function and decreased development of reactive fibrosis following myocardial infarction. These findings support the concept that adenosine signaling via the A 2B receptor contributes to post-infarction heart failure and adverse cardiac remodeling. This research has received full or partial funding support from the American Heart Association, AHA National Center.

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Autophagy modulation: a potential therapeutic approach in cardiac hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00145.2017 ◽

2017 ◽

Vol 313 (2) ◽

pp. H304-H319 ◽

Cited By ~ 37

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.

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Dysautonomia Due to Reduced Cholinergic Neurotransmission Causes Cardiac Remodeling and Heart Failure

Molecular and Cellular Biology ◽

10.1128/mcb.00996-09 ◽

2010 ◽

Vol 30 (7) ◽

pp. 1746-1756 ◽

Cited By ~ 49

Author(s):

Aline Lara ◽

Denis D. Damasceno ◽

Rita Pires ◽

Robert Gros ◽

Enéas R. Gomes ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Remodeling ◽

Mutant Mice ◽

Calcium Handling ◽

Cholinergic Neurotransmission ◽

Cardiac Phenotype ◽

Overwhelming Evidence ◽

Cholinergic Tone ◽

Release Of Acetylcholine

ABSTRACT Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure. In contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. By using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter (VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of altered cholinergic tone for cardiac function. M-mode echocardiography, hemodynamic experiments, analysis of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant mice have decreased left ventricle function associated with altered calcium handling. Gene expression was analyzed by quantitative reverse transcriptase PCR and Western blotting, and the results indicated that VAChT mutant mice have profound cardiac remodeling and reactivation of the fetal gene program. This phenotype was attributable to reduced cholinergic tone, since administration of the cholinesterase inhibitor pyridostigmine for 2 weeks reversed the cardiac phenotype in mutant mice. Our findings provide direct evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic alterations that contribute to heart dysfunction.

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The role of the cardiac lymphatic system in the development and progression of heart failure and novel therapeutic approaches for its management in post-infarction cardiac remodeling

CARDIOVASCULAR THERAPY AND PREVENTION ◽

10.15829/1728-8800-2020-2281 ◽

2020 ◽

Vol 19 (3) ◽

pp. 2281

Author(s):

Yu. S. Korneva ◽

R. V. Ukrainets

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Cardiac Remodeling ◽

Lymphatic Vessels ◽

Myocardial Damage ◽

Myocardial Edema ◽

Experimental Models ◽

Vital Role ◽

Treatment Regimens

Cardiac lymphatic vessels play a vital role in maintaining homeostasis in both physiological and pathological conditions, providing outflow of metabolites. It has been shown that myocardial infarction and postinfarction cardiac remodeling is accompanied by the lymphatic remodeling, which entails functional disorders and is of great importance in heart failure pathogenesis. As a result of progressive myocardial edema, hypoxia and fibrosis of the interstitial space increase, aggravating edema. Other pathways of additional myocardial damage and contractility reduction are triggered. Lymphatic efflux is associated with arrhythmias. Experimental models showed the positive effect of exogenous activation of lymphangiogenesis in relation to the prevention and treatment of heart failure, which can be further used to improve treatment regimens. This review discusses cardiac lymphatic remodeling after myocardial infarction, as well as the pathogenesis of related complications.

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The Role of Nrf2-Mediated Pathway in Cardiac Remodeling and Heart Failure

Oxidative Medicine and Cellular Longevity ◽

10.1155/2014/260429 ◽

2014 ◽

Vol 2014 ◽

pp. 1-16 ◽

Cited By ~ 58

Author(s):

Shanshan Zhou ◽

Wanqing Sun ◽

Zhiguo Zhang ◽

Yang Zheng

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Cardiac Remodeling ◽

Target Genes ◽

Cellular Tissue ◽

Antioxidant Defenses ◽

Related Factor ◽

Antioxidant Genes ◽

Endogenous Antioxidant

Heart failure (HF) is frequently the consequence of sustained, abnormal neurohormonal, and mechanical stress and remains a leading cause of death worldwide. The key pathophysiological process leading to HF is cardiac remodeling, a term referring to maladaptation to cardiac stress at the molecular, cellular, tissue, and organ levels. HF and many of the conditions that predispose one to HF are associated with oxidative stress. Increased generation of reactive oxygen species (ROS) in the heart can directly lead to increased necrosis and apoptosis of cardiomyocytes which subsequently induce cardiac remodeling and dysfunction. Nuclear factor-erythroid-2- (NF-E2-) related factor 2 (Nrf2) is a transcription factor that controls the basal and inducible expression of a battery of antioxidant genes and other cytoprotective phase II detoxifying enzymes that are ubiquitously expressed in the cardiovascular system. Emerging evidence has revealed that Nrf2 and its target genes are critical regulators of cardiovascular homeostasis via the suppression of oxidative stress, which is the key player in the development and progression of HF. The purpose of this review is to summarize evidence that activation of Nrf2 enhances endogenous antioxidant defenses and counteracts oxidative stress-associated cardiac remodeling and HF.

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