scholarly journals Osteopontin RNA aptamer can prevent and reverse pressure overload-induced heart failure

2017 ◽  
Vol 113 (6) ◽  
pp. 633-643 ◽  
Author(s):  
Jihe Li ◽  
Keyvan Yousefi ◽  
Wen Ding ◽  
Jayanti Singh ◽  
Lina A. Shehadeh
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Cardiomyocyte Hypertrophy ◽  
Therapeutic Effects ◽  
Rna Aptamer ◽  
Myocyte Hypertrophy

Aims Cardiac myocyte hypertrophy, the main compensatory response to chronic stress in the heart often progresses to a state of decompensation that can lead to heart failure. Osteopontin (OPN) is an effector for extracellular signalling that induces myocyte growth and fibrosis. Although increased OPN activity has been observed in stressed myocytes and fibroblasts, the detailed and long term effects of blocking OPN signalling on the heart remain poorly defined. Targeting cardiac OPN protein by an RNA aptamer may be beneficial for tuning down OPN pathologic signalling. We aimed to demonstrate the therapeutic effects of an OPN RNA aptamer on cardiac dysfunction. Methods and results In vivo, we show that in a mouse model of pressure overload, treating at the time of surgeries with an OPN aptamer prevented cardiomyocyte hypertrophy and cardiac fibrosis, blocked OPN downstream signalling (PI3K and Akt phosphorylation), reduced expression of extracellular matrix (Lum, Col3a1, Fn1) and hypertrophy (Nppa, Nppb) genes, and prevented cardiac dysfunction. Treating at two months post-surgeries with the OPN aptamer reversed cardiac dysfunction and fibrosis and myocyte hypertrophy. While genetic homozygous deletion of OPN reduced myocardial wall thickness, surprisingly cardiac function and myocardial fibrosis, specifically collagen deposition and myofibroblast infiltration, were worse compared with wild type mice at three months of pressure overload. Conclusion Taken together, these data demonstrate that tuning down cardiac OPN signalling by an OPN RNA aptamer is a novel and effective approach for preventing cardiac hypertrophy and fibrosis, improving cardiac function, and reversing pressure overload-induced heart failure.

Abstract 13810: TT-00920, a Clinical Stage Novel Phosphodiesterase 9 Inhibitor, Protects Against Heart Failure in a Rat Model of Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zejuan Sheng ◽  
Xiaoyan Qiang ◽  
Guoyu Li ◽  
Huimin Wang ◽  
Wenxin Dong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Rat Model ◽  
Cardiac Fibrosis ◽  
Clinical Stage ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Therapeutic Effects ◽  
Dependent Manner

Introduction: Phosphodiesterase 9 (PDE9) controls natriuretic-peptide-stimulated cyclic guanosine monophosphate in cardiac myocytes and is stongly upregulated in human heart failure, suggesting its potential as a promising therapeutic target in heart failure. Here we investigated the potential effects of TT-00920, a clinical stage novel and highly selective PDE9 inhibitor, on heart failure in a rat model of myocardial infarction. Methods: Myocardial infarction was induced by left anterior descending coronary artery (LAD) ligation in male Sprague Dawley rats. After 4-week treatment of vehicle, LCZ696, TT-00920, or TT-00920/Valsartan by oral gavage, efficacy was assessed by echocardiography and cardiac histopathology. Results: TT-00920 had remarkably improved cardiac function, protected against cardiac remodeling and fibrosis in a dose-dependent manner. TT-00920/Valsartan combination showed superior beneficial efficacy when compared to TT-00920 or LCZ696 single agent.Figure 1. TT-00920 improved cardiac function and ventricular remodeling.Figure 2. TT-00920 attenuated cardiac fibrosis in peri-infarct zone. Conclusions: TT-00920 reversed LAD-induced left ventricular dysfunction and remodeling, supporting its potential as a novel therapeutic agent for heart failure. The superior efficacy of TT-00920/Valsartan combination suggests that TT-00920 and renin-angiotensin-aldosterone system inhibitors may have additive therapeutic effects in heart failure.TT-00920 is currently being evaluated in Phase 1 clinical study for safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers (NCT04364789).

Abstract 50: Therapeutic Silencing of miRNA-652 Restores Cardiac Function and Attenuates Pathological Remodeling in a Mouse Model of Pressure Overload

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Bianca C Bernardo ◽  
Sally S Nguyen ◽  
Catherine E Winbanks ◽  
Xiao-Ming Gao ◽  
Esther J Boey ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Heart Function ◽  
Pressure Overload ◽  
Post Treatment ◽  
Locked Nucleic Acid ◽  
Luciferase Assay ◽  
Sham Operation

Introduction: Targeting microRNAs differentially regulated in settings of stress and protection could represent a new approach for the treatment of heart failure. miR-652 expression increased in hearts of a cardiac stress mouse model and was downregulated in a model of cardiac protection. Aim: To assess the therapeutic potential of silencing miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Methods: Mice were subjected to a sham operation (n=10) or transverse aortic constriction (TAC, n=14) for 4 weeks to induce hypertrophy and cardiac dysfunction. Mice were subcutaneously administered a locked nucleic acid (LNA)-antimiR-652 or LNA-control. Cardiac function was assessed by echocardiography before and 8 weeks post treatment, followed by molecular and histological analyses. Results: Expression of miR-652 increased in hearts subjected to pressure overload compared to sham operated mice (2.9 fold, n=3-5, P<0.05), but was silenced in hearts of mice administered LNA-antimiR-652 (95% decrease, n=3-7, P<0.05). In mice subjected to pressure overload, inhibition of miR-652 improved cardiac function (29±1% at 4 weeks post TAC compared to 35±1% post treatment, n=7, P<0.001) and attenuated cardiac hypertrophy. Functional and morphologic improvements in hearts of treated mice were associated with reduced cardiac fibrosis, apoptosis, cardiomyocyte size; decreased B-type natriuretic peptide gene expression; and preserved angiogenesis (all P<0.05, n=4-7/group). Mechanistically, we identified Jagged1, a Notch1 ligand, as a direct target of miR-652 by luciferase assay. Jagged1 and Notch1 mRNA were upregulated in hearts of TAC treated mice (1.2-1.7 fold, n=7, P<0.05). Importantly, chronic knockdown of miR-652 was not associated with any notable toxicity in other tissues. Conclusion: Therapeutic silencing of miR-652 protects the heart against pathological cardiac remodeling and improves heart function via mechanisms that are associated with preserved angiogenesis, decreased fibrosis and upregulation of a miR-652 target, Jagged1. These studies provide the first evidence that targeted inhibition of miR-652 could represent an attractive approach for the treatment of heart failure.

Abstract 069: Mitochondrial Mechanisms Of Reverse Remodeling In Heart Failure

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Preeti Ahuja ◽  
William R MacLellan ◽  
Yibin Wang
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Reverse Remodeling ◽  
Ventricular Assist ◽  
Hypertrophic Response ◽  
Mtdna Deletions ◽  
And Function

Enhancement of myocardial mitochondrial (mt) function resulting in efficient energy production by means of Left ventricular assist device (LVAD) has been suggested in heart failure (HF) which could have important clinical implications and may represent a novel therapeutic target. However, the basis for this improvement remains unknown. To characterize mt biogenesis, mt genomic integrity and mitophagy in reversing pathological remodeling, we investigated LV tissue from post-LVAD human hearts and after reversal of transaortic constriction (TAC) in mice. In Post-LVAD human hearts there was increased expression of mt fusion and biogenesis, mtDNA levels were normalized and deletion mutation rates were significantly reduced with reverse remodeling and these changes were associated with enhancement of mt ETC complex I and II activities and improved cardiac-myocyte morphology. To better understand the mechanisms underlying mt repair/remodeling with LVAD support, we developed a model of aortic banding (AB) and debanding (DB) in mice. C57BL/6 mice were subjected to 2 weeks of AB and subsequent DB for period of 1 to 20 days and cardiac function and hypertrophy were evaluated by echocardiography and real-time PCR, respectively. Compared with control animals, mice that had undergone banding had a robust hypertrophic response with decline in cardiac function. These parameters were reversed following removal of pressure overload by DB. Even 1 day of unloading led to significant increase in the expression of mt fusion and biogenesis genes. Hearts from AB (2 weeks) mice showed a 3.7-fold (P<0.05) increase in frequency of mtDNA deletions. However, mtDNA deletions were significantly reduced in frequency with DB when compared with AB hearts alone. Increase in expression of autophagy related genes could also be observed after hemodynamic unloading in mouse failing hearts. Removal of pressure overload by DB led to 2.58-fold (P<0.05) increase in expression of LC3B when compared to sham and AB mice. Thus, our data strongly suggest that protective effect of enhanced mt biogenesis, fusion/mtDNA repair and removal of damaged mitochondria by mitophagy could play an important role in maintaining mt integrity and function in the adult heart with reverse remodeling.

Inhibition of IκB phosphorylation prevents load-induced cardiac dysfunction in mice

2012 ◽  
Vol 303 (12) ◽  
pp. H1435-H1445 ◽  
Author(s):  
Tetsu Tanaka ◽  
Masahito Ogawa ◽  
Jun-ichi Suzuki ◽  
Asuka Sekinishi ◽  
Akiko Itai ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Nuclear Translocation ◽  
Pressure Overload ◽  
Treated Group ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
Cardiomyocyte Hypertrophy ◽  
Iκb Kinase

Pressure overload is known to be a cause of cardiac hypertrophy that often transits to heart failure. Although nuclear factor (NF)-κB is a key factor in the progression of cardiac hypertrophy, its pathophysiology is yet to be elucidated. Thus, we aimed to show that inhibition of NF-κB activation improves pressure overload-induced cardiac dysfunction. To assess the effect of inhibition on NF-κB activation in pressure overload cardiac hypertrophy, we used IMD-1041 in a murine thoracic aortic constriction (TAC) model. IMD-1041 inhibits the phosphorylation of IκB via inhibition of IκB kinase-β. IMD-1041 (100 mg·kg−1·day−1) or vehicle was administered orally into mice once a day, and mice were euthanized on day 42 after TAC. TAC resulted in left ventricular wall thickening, cardiac dysfunction, and increases of heart and lung weight, whereas IMD-1041 significantly suppressed the development of cardiac hypertropy 6 wk after TAC. Histologically, developed cardiac fibrosis and cardiomyocyte hypertrophy occurred in the vehicle-treated group, whereas IMD-1041 significantly attenuated these changes. IMD-1041 suppressed the expression of p65-positive cells and nuclear translocation of p65 induced by TAC compared with vehicle. Matrix metalloproteinase-2 activity increased in the vehicle + TAC-treated group; however, it was suppressed in the IMD-1041 + TAC-treated group. IMD-1041 treatment from day 28 to day 42 after TAC significantly attenuated the decrease in the percentage of fractional shortening and cardiac fibrosis without an antihypertrophic effect. In conclusion, IMD-1041 may be useful for preventing pressure overload-induced cardiac dysfunction and the transition of cardiac hypertrophy to contraction failure via suppression of NF-κB activation.

scholarly journals Distinct Phenotypes Induced by Different Degrees of Transverse Aortic Constriction in C57BL/6N Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Haiyan Deng ◽  
Lei-Lei Ma ◽  
Fei-Juan Kong ◽  
Zengyong Qiao
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Disease Model ◽  
Pressure Overload ◽  
Mouse Strains ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
The Difference

The transverse aortic constriction (TAC) model surgery is a widely used disease model to study pressure overload–induced cardiac hypertrophy and heart failure in mice. The severity of adverse cardiac remodeling of the TAC model is largely dependent on the degree of constriction around the aorta, and the phenotypes of TAC are also different in different mouse strains. Few studies focus on directly comparing phenotypes of the TAC model with different degrees of constriction around the aorta, and no study compares the difference in C57BL/6N mice. In the present study, C57BL/6N mice aged 10 weeks were subjected to sham, 25G TAC, 26G TAC, and 27G TAC surgery for 4 weeks. We then analyzed the different phenotypes induced by 25G TAC, 26G TAC, and 27G TAC in c57BL/6N mice in terms of pressure gradient, cardiac hypertrophy, cardiac function, heart failure situation, survival condition, and cardiac fibrosis. All C57BL/6N mice subjected to TAC surgery developed significantly hypertrophy. Mice subjected to 27G TAC had severe cardiac dysfunction, severe cardiac fibrosis, and exhibited characteristics of heart failure at 4 weeks post-TAC. Compared with 27G TAC mice, 26G TAC mice showed a much milder response in cardiac dysfunction and cardiac fibrosis compared to 27G TAC, and a very small fraction of the 26G TAC group exhibited characteristics of heart failure. There was no obvious cardiac dysfunction, cardiac fibrosis, and characteristics of heart failure observed in 25G TAC mice. Based on our results, we conclude that the 25G TAC, 26G TAC, and 27G TAC induced distinct phenotypes in C57BL/6N mice.

Abstract 409: Matrix Metalloproteinase-13 Inhibition is Protective in a Pressure Overload Model of Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Allison E Schafer ◽  
Iñigo Valiente-Alandi ◽  
Burns C Blaxall
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Proteolytic Enzymes ◽  
Ischemia Reperfusion ◽  
Pressure Overload ◽  
The United States ◽  
Cardiac Cells ◽  
Ecm Proteins

Heart failure (HF), the leading cause of morbidity and mortality in the United States, is characterized by pathologic remodeling, fibrosis and deteriorating cardiac function. Cardiac fibrosis occurs due to imbalanced production and degradation of extracellular matrix (ECM) proteins. Cardiac fibroblasts (CF) are largely responsible for the secretion of ECM proteins in the heart, and upon injury, transition to a migratory and proliferative myofibroblast (MF) phenotype, leading to excess ECM deposition. Elevated expression of matrix metalloproteinases (MMPs), proteolytic enzymes responsible for degradation of the ECM, is common in HF. Specifically, MMP13 is known to be upregulated in human HF patients. Therefore, we hypothesized that MMP13 plays an important role in pathologic cardiac remodeling, and that inhibition of MMP13 would prevent the development of HF in a pressure overload model, transverse aortic constriction (TAC). Mice were subjected to TAC and treated with the MMP13 inhibitor, WAY170523 (WAY), or vehicle 4 weeks post-TAC until 12 weeks post-TAC. Mice treated with WAY display decreased cardiac hypertrophy and preserved cardiac function compared to vehicle treated mice. WAY treatment may also attenuate interstitial and perivascular fibrosis as well as expression of pro-fibrotic genes. To determine the effect of MMP13 inhibition in cardiac cells, CF and MF were isolated from healthy mice or mice 5 days post-ischemia/reperfusion injury, respectively, and treated with WAY. MMP13 inhibition led to decreased CF invasion but did not affect migration, proliferation or adhesion. Interestingly, inhibition of MMP13 in MF attenuated migration, proliferation and invasion. Moreover, WAY treatment reduced collagen and fibronectin deposition in the ECM of MF. MMP13 inhibition also appeared to decrease Angiotensin II-induced hypertrophy in ventricular cardiomyocytes (CM). These data suggest a role for MMP13 in pressure overload-induced HF, CM hypertrophy and CF behavior. MMP13 inhibition after injury may attenuate cardiac hypertrophy as well as the CF to MF transition, leading to decreased cardiac fibrosis and improved cardiac function. Further understanding of the role of MMP13 could lead to a novel therapeutic target in the treatment of HF.

scholarly journals Decreased metalloprotease 9 induction, cardiac fibrosis, and higher autophagy after pressure overload in mice lacking the transcriptional regulator p8

2011 ◽  
Vol 301 (5) ◽  
pp. C1046-C1056 ◽  
Author(s):  
Serban P. Georgescu ◽  
Mark J. Aronovitz ◽  
Juan L. Iovanna ◽  
Richard D. Patten ◽  
John M. Kyriakis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Pressure Overload ◽  
Transcriptional Regulator ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Causative Role

Left ventricular remodeling, including the deposition of excess extracellular matrix, is key to the pathogenesis of heart failure. The stress-inducible transcriptional regulator p8 is increased in failing human hearts and is required both for agonist-stimulated cardiomyocyte hypertrophy and for cardiac fibroblasts matrix metalloprotease-9 (MMP9) induction. In the heart, upregulation of autophagy is an adaptive response to stress and plays a causative role in cardiomyopathies. We have recently shown that p8 ablation in cardiac cells upregulates autophagy and that, in vivo, loss of p8 results in a decrease of cardiac function. Here we investigated the effects of p8 genetic deletion in mediating adverse myocardial remodeling. Unstressed p8−/− mouse hearts manifested complex alterations in the expression of fibrosis markers. In addition, these mice displayed elevated autophagy and apoptosis compared with p8+/+ mice. Transverse aortic constriction (TAC) induced left ventricular p8 expression in p8+/+ mice. Pressure overload caused left ventricular remodeling in both genotypes, however, p8−/− mice showed less cardiac fibrosis induction. Consistent with this, although MMP9 induction was attenuated in the p8−/− mice, induction of MMP2 and MMP3 were strikingly upregulated while TIMP2 was downregulated. Left ventricular autophagy increased after TAC and was significantly higher in the p8−/− mice. Thus p8-deletion results in reduced collagen fibrosis after TAC, but in turn, is associated with a detrimental higher increase in autophagy. These findings suggest a role for p8 in regulating in vivo key signaling pathways involved in the pathogenesis of heart failure.

Inhibition of NOS II prevents cardiac dysfunction in myocardial infarction and congestive heart failure

2002 ◽  
Vol 283 (1) ◽  
pp. H339-H345 ◽  
Author(s):  
Takayuki Saito ◽  
Fu Hu ◽  
Lara Tayara ◽  
Linda Fahas ◽  
Hani Shennib ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Congestive Heart Failure ◽  
Cardiac Function ◽  
Infarct Size ◽  
Cardiac Dysfunction ◽  
Cardiomyocyte Hypertrophy ◽  
Lung Water ◽  
Term Administration

Strong expression of the inducible form of nitric oxide synthase (NOS II) has been shown in the myocardium of patients with myocardial infarction (MI). We hypothesized that NOS II plays an important role in the development of MI and subsequent heart failure and that inhibition of NOS II may beneficially alter the course of the disease. Long-term administration (2 mo) of the selective NOS II inhibitor S-methylisothiourea (SMT) to rats with MI significantly improved cardiac function. A significant drop in mortality, lung water content, infarct size, and cardiomyocyte hypertrophy was also associated with the use of SMT. Plasma concentration of nitrite and nitrate was also reduced by SMT. Short-term administration of SMT (first 2 wk only) significantly reduced infarct size; however, it did not improve cardiac dysfunction measured 2 mo after MI. These findings demonstrate that induction of NOS II during MI exerts negative effects on cardiac function and structure. Long-term administration of a selective NOS II inhibitor may prove to be beneficial in the treatment of MI and congestive heart failure.

Exercise cardiac MRI unmasks cardiac dysfunction in childhood and adolescent cancer survivors with reduced cardiopulmonary fitness

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Foulkes ◽  
B Costello ◽  
E.J Howden ◽  
K Janssens ◽  
H Dillon ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cancer Survivors ◽  
Pediatric Cancer ◽  
Cardiac Dysfunction ◽  
Cardiopulmonary Fitness ◽  
Cardiac Reserve ◽  
Pediatric Cancer Survivors ◽  
Increased Risk

Abstract Background Young cancer survivors are at increased risk of impaired cardiopulmonary fitness (VO2peak) and heart failure. Assessment of exercise cardiac reserve may reveal sub-clinical abnormalities that better explain impairments in fitness and long term heart failure risk. Purpose To investigate the presence of impaired VO2peak in pediatric cancer survivors with increased risk of heart failure, and to assess its relationship with resting cardiac function and cardiac reserve Methods Twenty pediatric cancer survivors (aged 8–24 years) treated with anthracycline chemotherapy underwent cardiopulmonary exercise testing to quantify VO2peak, with a value &lt;85% of predicted defined as impaired VO2peak. Resting cardiac function was assessed using 3-dimensional echocardiography, with cardiac reserve quantified from resting and peak exercise heart rate (HR), stroke volume index (SVi) and cardiac index (CI) using exercise cardiac magnetic resonance imaging. Results 12 of 20 survivors (60%) had impaired VO2peak (97±14% vs. 70±16% of age and gender predicted). There were no differences in echocardiographic or CMR measurements of resting cardiac function between survivors with normal or impaired VO2peak. However, those with reduced VO2peak had diminished cardiac reserve, with a lesser increase in CI (Fig. 1A) and SVi (Fig. 1B) during exercise (Interaction P=0.001 for both), whilst the HR response was similar (Fig. 1C; P=0.71). Conclusions Resting measures of cardiac function are insensitive to significant cardiac dysfunction amongst pediatric cancer survivors with reduced VO2peak. Measures of cardiopulmonary fitness and cardiac reserve may aid in early identification of survivors with heightened risk of long-term heart failure. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Heart Foundation

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.

Sign in / Sign up

Export Citation Format

Share Document