Abstract 375: Mechanotransduction via Titin’s N2B Element Contributes to Cardiac Remodeling

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Mathew Bull ◽  
Pooja Nair ◽  
Joshua Strom ◽  
Michael Gotthardt ◽  
Henk Granzier
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Mapk Pathway ◽  
Hot Spot ◽  
Pressure Overload ◽  
Volume Overload ◽  
Mitogen Activated Protein Kinase ◽  
Stress And Strain ◽  
Knock Out ◽  
Voluntary Running

Pathological remodeling is responsible for the functional deficits characteristic of heart failure patients. Understanding mechanotransduction is limited, but holds potential to provide novel therapeutic targets to treat patients with heart failure, especially those with diastolic dysfunction and preserved ejection fraction (HFpEF). Titin is the largest known protein and is abundant in muscle. It is the main contributor of passive stiffness in the heart and functions as a molecular mechano-sensor for stress and strain in the myocyte. Titin is composed of four distinct regions, (N-terminal Z-line, I-band, A-band, and C-terminal M-line), and acts as a molecular spring that is responsible for the assembly and maintenance of ultrastructure in the sarcomere. The elastic N2B element found in titin’s I-band region has been proposed as a mechano-sensor and signaling “hot spot” in the sarcomere. This study investigates the role of titin’s cardiac specific N2B element as sensor for stress and strain induced remodeling in the heart. The previously published N2B knock out (KO) mouse was subjected to a variety of stressors including transverse aortic constriction (TAC), aorto-caval fistula (ACF), chronic swimming, voluntary running and isoproterenol injections. Through chronic pathologic stress, pressure overload (TAC) and chronic volume overload (ACF), we found that the N2B element is necessary for the response to volume overload but not pressure overload as determined by changes in cardiac remodeling. Furthermore, the response to exercise either by chronic swimming or voluntary running was reduced in the N2B KO mouse. Finally, unlike the wild-type (WT) mouse, the N2B KO mouse did not respond to isoproterenol injections with hypertrophic remodeling. Ongoing work to elucidate the molecular pathways involving the N2B element and response to stress, is focused on its binding protein Four-and-a-half-LIM domains 2 (FHL2) and the mitogen activated protein kinase (MAPK) pathway. Taken together our data suggest that the N2B element contributes significantly to mechanotransduction in the heart.

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.

scholarly journals TVP1022 Attenuates Cardiac Remodeling and Kidney Dysfunction in Experimental Volume Overload-Induced Congestive Heart Failure

2011 ◽  
Vol 4 (4) ◽  
pp. 463-473 ◽  
Author(s):  
Zaid A. Abassi ◽  
Yaron D. Barac ◽  
Sawa Kostin ◽  
Ariel Roguin ◽  
Elena Ovcharenko ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Cardiac Remodeling ◽  
Volume Overload ◽  
Kidney Dysfunction

Abstract 14952: Hemodynamic Comparison of Left Ventricular Function in Pressure Overload- versus Volume Overload-Induced Heart Failure Models by Invasive Pressure-Volume Analysis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Mihály Ruppert ◽  
Christian Karime ◽  
Alex A Sayour ◽  
Attila Oláh ◽  
Dávid Nagy ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systolic Function ◽  
Pressure Overload ◽  
Volume Overload ◽  
Detailed Comparison ◽  
Left Ventricular ◽  
Lv Function ◽  
Arterial Elastance ◽  
Lv Remodeling ◽  
Av Shunt

Introduction: Both sustained left ventricular (LV) pressure overload (PO) and volume overload (VO) induces LV remodeling and eventually development of heart failure (HF). Using rat models, the present study aimed to provide a detailed comparison of distinct aspects of LV function in PO- and VO-induced HF. Methods: PO and VO was induced by transverse aortic constriction (TAC, n=12) and aortocaval shunt (AV-shunt, n=12) creation respectively. Controls underwent corresponding sham operations (n=11). LV remodeling was characterized by echocardiography, histology, qRT PCR, and western blot. LV function was assessed by invasive pressure-volume (P-V) analysis. Results: Both sustained PO and VO resulted in the development of HF, as evidenced by increased LV BNP mRNA expression, pulmonary edema, and characteristic symptoms. While the extent of LV hypertrophy was comparable between the HF models, PO induced concentric while VO evoked eccentric LV remodeling. P-V analysis revealed impaired systolic function in both HF models. Accordingly, decreased ejection fraction and impaired ventriculo-arterial coupling (calculated as the ratio of arterial elastance/LV contractility [VAC]: 0.38±0.05 vs. 1.30±0.13, ShamTAC vs. TAC and 0.52±0.08 vs. 1.17±0.13, ShamAV-Shunt vs. AV-shunt; p<0.05) was detected in both HF models. However, in case of VO the severely reduced LV contractility (slope of end-systolic P-V relationship: 1.79±0.19 vs. 0.52±0.06, ShamAV-Shunt vs. AV-shunt, p<0.05 and 2.14±0.28 vs. 2.03±0.21, ShamTAC vs. TAC p>0.05) underpinned the contractility-afterload mismatch, while in case of PO the increased afterload (arterial elastance: 0.77±0.07 vs. 2.64±0.28, ShamTAC vs. TAC and 0.80±0.07 vs. 0.54±0.05, ShamAV-Shunt vs. AV-shunt; p<0.05) was the main determinant. Furthermore, prolongation of active relaxation occurred to a greater extent in case of PO. In addition, increased myocardial stiffness was only observed in PO-induced HF. Conclusion: Systolic function was reduced in both HF models. However, different factors underpinned the impaired VAC in case of VO (reduced LV contractility) and PO (increased arterial elastance). Furthermore, although diastolic function deteriorated in both models, it occurred to a greater extent in case of PO.

Abstract 354: The Role of the Liver Heart Axis During Cardiac Remodeling

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Soichiro Usui ◽  
Shin-ichiro Takashima ◽  
Kenji Sakata ◽  
Masa-aki Kawashiri ◽  
Masayuki Takamura
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Normal Subjects ◽  
Serum Levels ◽  
Lung Weight ◽  
Reduced Ejection Fraction ◽  
Hepatic Expression

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.

3,3-Dimethyl-1-butanol attenuates cardiac remodeling in pressure-overload-induced heart failure mice

2020 ◽  
Vol 78 ◽  
pp. 108341 ◽  
Author(s):  
Guangji Wang ◽  
Bin Kong ◽  
Wei Shuai ◽  
Hui Fu ◽  
Xiaobo Jiang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Pressure Overload

scholarly journals Proteasome inhibition decreases cardiac remodeling after initiation of pressure overload

2008 ◽  
Vol 295 (4) ◽  
pp. H1385-H1393 ◽  
Author(s):  
Nadia Hedhli ◽  
Paulo Lizano ◽  
Chull Hong ◽  
Luke F. Fritzky ◽  
Sunil K. Dhar ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Remodeling ◽  
Ventricular Remodeling ◽  
Pressure Overload ◽  
Proteasome Inhibition ◽  
Aortic Banding ◽  
Lung Weight ◽  
Cross Sectional ◽  
Myocyte Apoptosis

We tested the possibility that proteasome inhibition may reverse preexisting cardiac hypertrophy and improve remodeling upon pressure overload. Mice were submitted to aortic banding and followed up for 3 wk. The proteasome inhibitor epoxomicin (0.5 mg/kg) or the vehicle was injected daily, starting 2 wk after banding. At the end of the third week, vehicle-treated banded animals showed significant ( P < 0.05) increase in proteasome activity (PA), left ventricle-to-tibial length ratio (LV/TL), myocyte cross-sectional area (MCA), and myocyte apoptosis compared with sham-operated animals and developed signs of heart failure, including increased lung weight-to-TL ratio and decreased ejection fraction. When compared with that group, banded mice treated with epoxomicin showed no increase in PA, a lower LV/TL and MCA, reduced apoptosis, stabilized ejection fraction, and no signs of heart failure. Because overload-mediated cardiac remodeling largely depends on the activation of the proteasome-regulated transcription factor NF-κB, we tested whether epoxomicin would prevent this activation. NF-κB activity increased significantly upon overload, which was suppressed by epoxomicin. The expression of NF-κB-dependent transcripts, encoding collagen types I and III and the matrix metalloprotease-2, increased ( P < 0.05) after banding, which was abolished by epoxomicin. The accumulation of collagen after overload, as measured by histology, was 75% lower ( P < 0.05) with epoxomicin compared with vehicle. Myocyte apoptosis increased by fourfold in hearts submitted to aortic banding compared with sham-operated hearts, which was reduced by half upon epoxomicin treatment. Therefore, we propose that proteasome inhibition after the onset of pressure overload rescues ventricular remodeling by stabilizing cardiac function, suppressing further progression of hypertrophy, repressing collagen accumulation, and reducing myocyte apoptosis.

Ketone Body Metabolism Attenuates Oxidative Stress and Cardiac Remodeling in Pressure Overload Heart Failure

2014 ◽  
Vol 20 (10) ◽  
pp. S204
Author(s):  
Motoki Uchihashi ◽  
Atsushi Hoshino ◽  
Makoto Ariyoshi ◽  
Shuhei Tateishi ◽  
Kazunori Ono ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Remodeling ◽  
Ketone Body ◽  
Pressure Overload ◽  
Ketone Body Metabolism

scholarly journals A Review of the Molecular Mechanisms Underlying the Development and Progression of Cardiac Remodeling

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Leonardo Schirone ◽  
Maurizio Forte ◽  
Silvia Palmerio ◽  
Derek Yee ◽  
Cristina Nocella ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Remodeling ◽  
Molecular Mechanisms ◽  
Volume Overload ◽  
Cardiac Complications ◽  
Compensatory Mechanism ◽  
Myocardial Remodeling ◽  
Heart Failure Progression ◽  
Complex Signaling

Pathological molecular mechanisms involved in myocardial remodeling contribute to alter the existing structure of the heart, leading to cardiac dysfunction. Among the complex signaling network that characterizes myocardial remodeling, the distinct processes are myocyte loss, cardiac hypertrophy, alteration of extracellular matrix homeostasis, fibrosis, defective autophagy, metabolic abnormalities, and mitochondrial dysfunction. Several pathophysiological stimuli, such as pressure and volume overload, trigger the remodeling cascade, a process that initially confers protection to the heart as a compensatory mechanism. Yet chronic inflammation after myocardial infarction also leads to cardiac remodeling that, when prolonged, leads to heart failure progression. Here, we review the molecular pathways involved in cardiac remodeling, with particular emphasis on those associated with myocardial infarction. A better understanding of cell signaling involved in cardiac remodeling may support the development of new therapeutic strategies towards the treatment of heart failure and reduction of cardiac complications. We will also discuss data derived from gene therapy approaches for modulating key mediators of cardiac remodeling.

scholarly journals Alleviation of Inflammation and Oxidative Stress in Pressure Overload-Induced Cardiac Remodeling and Heart Failure via IL-6/STAT3 Inhibition by Raloxifene

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Shengqi Huo ◽  
Wei Shi ◽  
Haiyan Ma ◽  
Dan Yan ◽  
Pengcheng Luo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Protein Expression ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Stat3 Signaling ◽  
H9c2 Myoblasts ◽  
And Oxidative Stress ◽  
Stat3 Inhibition

Background. Inflammation and oxidative stress are involved in the initiation and progress of heart failure (HF). However, the role of the IL6/STAT3 pathway in the pressure overload-induced HF remains controversial. Methods and Results. Transverse aortic constriction (TAC) was used to induce pressure overload-HF in C57BL/6J mice. 18 mice were randomized into three groups (Sham, TAC, and TAC+raloxifene, n = 6 , respectively). Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in the myocardium. TAC (four and eight weeks) elevated the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and prohibitin2 (PHB2) protein expression. Importantly, IL-6/gp130/STAT3 inhibition by raloxifene alleviated TAC-induced myocardial inflammation, cardiac remodeling, and dysfunction. In vitro, we demonstrated cellular hypertrophy with STAT3 activation and oxidative stress exacerbation could be elicited by IL-6 (25 ng/mL, 48 h) in H9c2 myoblasts. Sustained IL-6 stimulation increased intracellular reactive oxygen species, repressed mitochondrial membrane potential (MMP), decreased intracellular content of ATP, and led to decreased SOD activity, an increase in iNOS protein expression, and increased protein expression of Pink1, Parkin, and Bnip3 involving in mitophagy, all of which were reversed by raloxifene. Conclusion. Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF.

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