scholarly journals Estrogen deprivation aggravates cardiac hypertrophy in nonobese Type 2 diabetic Goto–Kakizaki (GK) rats

2017 ◽  
Vol 37 (5) ◽  
Author(s):  
Nattayaporn Apaijai ◽  
Narattaphol Charoenphandhu ◽  
Jitjiroj Ittichaichareon ◽  
Panan Suntornsaratoon ◽  
Nateetip Krishnamra ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Mitochondrial Dynamics ◽  
Sham Operation ◽  
Estrogen Deprivation ◽  
Gk Rats

Both Type 2 diabetes mellitus (T2DM) and estrogen deprivation have been shown to be associated with the development of cardiovascular disease and adverse cardiac remodeling. However, the role of estrogen deprivation on adverse cardiac remodeling in nonobese T2DM rats has not been clearly elucidated. We hypothesized that estrogen-deprivation aggravates adverse cardiac remodeling in Goto–Kakizaki (GK) rats. Wild-type (WT) and GK rats at the age of 9 months old were divided into two subgroups to have either a sham operation (WTS, GKS) or a bilateral ovariectomy (WTO, GKO) (n = 6/subgroup). Four months after the operation, the rats were killed, and the heart was excised rapidly. Metabolic parameters, cardiomyocytes hypertrophy, cardiac fibrosis, and biochemical parameters were determined. GK rats had hyperglycemia with hypoinsulinemia, and estrogen deprivation did not increase the severity of T2DM. Cardiac hypertrophy, cardiac oxidative stress, and phosphor-antinuclear factor κB were higher in WTO and GKS rats than WTS rats, and they markedly increased in GKO rats compared with GKS rats. Furthermore, cardiac fibrosis, transforming growth factor-β, Bax, phosphor-p38, and peroxisome proliferator- activated receptor γ coactivator-1α expression were increased in GKS and GKO rats compared with the lean rats. However, mitochondrial dynamics proteins including dynamin-related protein 1 and mitofusin-2 were not altered by T2DM and estrogen deprivation. Although estrogen deprivation did not aggravate T2DM in GK rats, it increased the severity of cardiac hypertrophy by provoking cardiac inflammation and oxidative stress in nonobese GK rats.

Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes

Diabetes ◽  
1999 ◽  
Vol 48 (4) ◽  
pp. 927-932 ◽  
Author(s):  
Y. Ihara ◽  
S. Toyokuni ◽  
K. Uchida ◽  
H. Odaka ◽  
T. Tanaka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Gk Rats

Oxidative Stress and Transforming Growth Factor-.β1-induced Cardiac Fibrosis

2013 ◽  
Vol 13 (2) ◽  
pp. 165-172 ◽  
Author(s):  
Yudi Purnomo ◽  
Yvette Piccart ◽  
Tamara Coenen ◽  
John Prihadi ◽  
Paul Lijnen
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor

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 14664: Reduced Activin Like Kinase 1 Activity Promotes Cardiac Fibrosis in Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Kevin Morine ◽  
Vikram Paruchuri ◽  
Xiaoying Qiao ◽  
Emily Mackey ◽  
Mark Aronovitz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Left Ventricular ◽  
Lv Function ◽  
Type I ◽  
Mrna Levels ◽  
Protein Levels

Introduction: Activin receptor like kinase 1 (ALK1) mediates signaling via transforming growth factor beta-1 (TGFb1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. Methods and Results: ALK1 mRNA expression was quantified by RT-PCR in left ventricular (LV) tissue from patients with end-stage heart failure and compared to control LV tissue obtained from the National Disease Research Interchange (n=8/group). Compared to controls, LV ALK1 mRNA levels were reduced by 85% in patients with heart failure. Next, using an siRNA approach, we tested whether reduced ALK1 levels promote TGFb1-mediated collagen production in human cardiac fibroblasts. Treatment with an ALK1 siRNA reduced ALK1 mRNA levels by 75%. Compared to control, TGFb1-mediated Type I collagen and pSmad-3 protein levels were 2.5-fold and 1.7-fold higher, respectively, after ALK1 depletion. To explore a role for ALK1 in heart failure, ALK1 haploinsufficient (ALK1) and wild-type mice (WT; n=8/group) were studied 2 weeks after thoracic aortic constriction (TAC). Compared to WT, baseline LV ALK1 mRNA levels were 50% lower in ALK1 mice. Both LV and lung weights were higher in ALK1 mice after TAC. Cardiomyocyte area and LV mRNA levels of BNP, RCAN, and b-MHC were increased similarly, while SERCa levels were reduced in both ALK1 and WT mice after TAC. Compared to WT, LV fibrosis (Figure) and Type 1 Collagen mRNA and protein levels were higher among ALK1 mice. Compared to WT, LV fractional shortening (48±12 vs 26±10%, p=0.01) and survival (Figure) were lower in ALK1 mice after TAC. Conclusions: Reduced LV expression of ALK1 is associated with advanced heart failure in humans and promotes early mortality, impaired LV function, and cardiac fibrosis in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.

scholarly journals MicroRNA-101a Inhibits Cardiac Fibrosis Induced by Hypoxia via Targeting TGFβRI on Cardiac Fibroblasts

2015 ◽  
Vol 35 (1) ◽  
pp. 213-226 ◽  
Author(s):  
Xin Zhao ◽  
Kejing Wang ◽  
Yuhua Liao ◽  
Qiutang Zeng ◽  
Yushu Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Luciferase Reporter ◽  
Migration Ability

Background/Aims: Hypoxia is a basic pathological challenge that is associated with numerous cardiovascular disorders including aberrant cardiac remodeling. Transforming growth factor beta (TGF-β) signaling pathway plays a pivotal role in mediating cardiac fibroblast (CF) function and cardiac fibrosis. Recent data suggested that microRNA-101a (miR-101a) exerted anti-fibrotic effects in post-infarct cardiac remodeling and improved cardiac function. This study aimed to investigate the potential relationship between hypoxia, miR-101a and TGF-β signaling pathway in CFs. Methods and Results: Two weeks following coronary artery occlusion in rats, the expression levels of both TGFβ1 and TGFβRI were increased, but the expression of miR-101a was decreased at the site of the infarct and along its border. Cultured rat neonatal CFs treated with hypoxia were characterized by the up-regulation of TGFβ1 and TGFβRI and the down-regulation of miR-101a. Delivery of miR-101a mimics significantly suppressed the expression of TGFβRI and p-Smad 3, CF differentiation and collagen content of CFs. These anti-fibrotic effects were abrogated by co-transfection with AMO-miR-101a, an antisense inhibitor of miR-101a. The repression of TGFβRI, a target of miR-101a, was validated by luciferase reporter assays targeting the 3'UTR of TGFβRI. Additionally, we found that overexpression of miR-101a reversed the improved migration ability of CFs and further reduced CF proliferation caused by hypoxia. Conclusion: Our study illustrates that miR-101a exerts anti-fibrotic effects by targeting TGFβRI, suggesting that miR-101a plays a multi-faceted role in modulating TGF-β signaling pathway and cardiac fibrosis.

scholarly journals Impact of Bariatric Surgery on Ghrelin and Obestatin Levels in Obesity or Type 2 Diabetes Mellitus Rat Model

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Donglei Zhou ◽  
Xun Jiang ◽  
Weixing Ding ◽  
Dingyu Zhang ◽  
Lei Yang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Bariatric Surgery ◽  
Type 2 Diabetes Mellitus ◽  
Weight Control ◽  
Sham Operation ◽  
Gk Rats ◽  
Obese Rats ◽  
To Receive

We aimed to evaluate the therapeutic efficacy on weight control by different bariatric surgeries and investigate the ghrelin and obestatin changes after these surgeries in obesity and nonobese type 2 diabetes mellitus (T2DM) rats. Obese rats were randomly assigned to receive sleeve gastrectomy (SG,n=8), minigastric bypass (MGBP,n=8), roux-en-Y gastric bypass (RYGBP,n=8), and sham operation (SO,n=4). Another 4 rats served as control. Besides, Goto-Kakisaki (GK) rats were also randomly divided into similar groups except for total gastrectomy (TG,n=8) group. The results showed that in obese rats, weigh loss in RYGBP group was similar to that in MGBP group but larger than that in SG group. Ghrelin significantly increased in RYGB group, but obestatin increased in MGBP group. Ghrelin/obestatin ratio significantly decreased in SG group. In GK rats, weight loss was most obvious in TG group. Postoperatively, ghrelin was significantly increased in MGBP and RYGB groups but decreased in TG group. Obestatin also showed an increase in MGBP and RYGB groups. Ghrelin/obestatin in TG group decreased significantly. In conclusion, RYGB and MGBP may be more suitable for obese rats, but TG may be the best strategy for T2DM rats to control weight with different mechanisms.

scholarly journals MicroRNA as a Therapeutic Target in Cardiac Remodeling

2017 ◽  
Vol 2017 ◽  
pp. 1-25 ◽  
Author(s):  
Chao Chen ◽  
Murugavel Ponnusamy ◽  
Cuiyun Liu ◽  
Jinning Gao ◽  
Kun Wang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Heart Diseases ◽  
Myocardial Remodeling ◽  
Cardiac Tissues ◽  
Rna Molecules ◽  
Mirnas Expression ◽  
The Impact

MicroRNAs (miRNAs) are small RNA molecules that contain 18–25 nucleotides. The alterations in their expression level play crucial role in the development of many disorders including heart diseases. Myocardial remodeling is the final pathological consequence of a variety of myocardial diseases. miRNAs have central role in regulating pathogenesis of myocardial remodeling by modulating cardiac hypertrophy, cardiomyocytes injury, cardiac fibrosis, angiogenesis, and inflammatory response through multiple mechanisms. The balancing and tight regulation of different miRNAs is a key to drive the cellular events towards functional recovery and any fall in this leads to detrimental effect on cardiac function following various insults. In this review, we discuss the impact of alterations of miRNAs expression on cardiac hypertrophy, cardiomyocytes injury, cardiac fibrosis, angiogenesis, and inflammatory response. We have also described the targets (receptors, signaling molecules, transcription factors, etc.) of miRNAs on which they act to promote or attenuate cardiac remodeling processes in different type cells of cardiac tissues.

scholarly journals Luteolin Improves Perivascular Adipose Tissue Profile and Vascular Dysfunction in Goto-Kakizaki Rats

2021 ◽  
Vol 22 (24) ◽  
pp. 13671
Author(s):  
Marcelo Queiroz ◽  
Adriana Leandro ◽  
Lara Azul ◽  
Artur Figueirinha ◽  
Raquel Seiça ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Endothelial Function ◽  
Metabolic Parameters ◽  
Perivascular Adipose Tissue ◽  
Gk Rats ◽  
Vascular Oxidative Stress ◽  
Luteolin Treatment

We investigated the effects of luteolin on metabolism, vascular reactivity, and perivascular adipose tissue (PVAT) in nonobese type 2 diabetes mellitus animal model, Goto-Kakizaki (GK) rats. Methods: Wistar and GK rats were divided in two groups: (1) control groups treated with vehicle; (2) groups treated with luteolin (10 mg/kg/day, for 2 months). Several metabolic parameters such as adiposity index, lipid profile, fasting glucose levels, glucose and insulin tolerance tests were determined. Endothelial function and contraction studies were performed in aortas with (PVAT+) or without (PVAT−) periaortic adipose tissue. We also studied vascular oxidative stress, glycation and assessed CRP, CCL2, and nitrotyrosine levels in PVAT. Results: Endothelial function was impaired in diabetic GK rats (47% (GK − PVAT) and 65% (GK + PVAT) inhibition of maximal endothelial dependent relaxation) and significantly improved by luteolin treatment (29% (GK − PVAT) and 22% (GK + PVAT) inhibition of maximal endothelial dependent relaxation, p < 0.01). Vascular oxidative stress and advanced glycation end-products’ levels were increased in aortic rings (~2-fold, p < 0.05) of diabetic rats and significantly improved by luteolin treatment (to levels not significantly different from controls). Periaortic adipose tissue anti-contractile action was significantly rescued with luteolin administration (p < 0.001). In addition, luteolin treatment significantly recovered proinflammatory and pro-oxidant PVAT phenotype, and improved systemic and metabolic parameters in GK rats. Conclusions: Luteolin ameliorates endothelial dysfunction in type 2 diabetes and exhibits therapeutic potential for the treatment of vascular complications associated with type 2 diabetes.

scholarly journals Hydrogen Sulfide Donor NaHS Improves Metabolism and Reduces Muscle Atrophy in Type 2 Diabetes: Implication for Understanding Sarcopenic Pathophysiology

2018 ◽  
Vol 2018 ◽  
pp. 1-17 ◽  
Author(s):  
Milad S. Bitar ◽  
Joelle Nader ◽  
Waleed Al-Ali ◽  
Ashraf Al Madhoun ◽  
Hossein Arefanian ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Hydrogen Sulfide ◽  
Muscle Mass ◽  
Early Stage ◽  
Current Data ◽  
Mtor Signaling ◽  
Gk Rats ◽  
S Deficiency

Sarcopenia, a loss of muscle mass and functionality, constitutes a major contributor to disability in diabetes. Hydrogen sulfide (H2S) dynamics and muscle mass regulatory signaling were studied in GK rats, a model for type 2 diabetes (T2D). GK rats exhibited a number of features that are consistent with sarcopenia and T2D including loss of muscle mass and strength, in addition to glucose intolerance, insulin resistance, and impaired β-cell responsiveness to glucose. Mechanistically, activation levels of Akt, a key modulator of protein balance, were decreased in T2D. Consequently, we confirmed reduced activity of mTOR signaling components and higher expression of atrophy-related markers typified by FoxO1/atrogin-1/MuRF1 and myostatin-Smad2/3 signaling during the course of diabetes. We observed in GK rat reduced antioxidant capacity (↓GSH/GSSG) and increased expression and activity of NADPH oxidase in connection with augmented rate of oxidation of lipids, proteins, and DNA. H2S bioavailability and the expression of key enzymes involved in its synthesis were suppressed as a function of diabetes. Interestingly, GK rats receiving NaHS displayed increased muscle Akt/mTOR signaling and decreased expression of myostatin and the FoxO1/MuRF1/atrogin-dependent pathway. Moreover, diabetes-induced heightened state of oxidative stress was also ameliorated in response to NaHS therapy. Overall, the current data support the notion that a relationship exists between sarcopenia, heightened state of oxidative stress, and H2S deficiency at least in the context of diabetes. Moreover, treatment with a potent H2S donor at an early stage of diabetes is likely to mitigate the development of sarcopenia/frailty and predictably reduces its devastating sequelae of amputation.

scholarly journals Angiotensin II receptor blocker LCZ696 attenuates cardiac remodeling through the inhibition of the ERK signaling pathway in mice with pregnancy-associated cardiomyopathy

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yi Wang ◽  
Zhiheng Guo ◽  
Yongmei Gao ◽  
Ping Liang ◽  
Yanhong Shan ◽  
...  
Keyword(s):  
Survival Rate ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Erk Signaling ◽  
Ang Ii ◽  
Total Survival

Abstract Pregnancy-associated cardiomyopathy (PAH) represents a pregnancy-associated myocardial disease that is characterized by the progression of heart failure due to marked left ventricular systolic dysfunction. Compelling evidence has highlighted the potential of angiotensin (Ang) receptor inhibitors as therapeutic targets in PAH treatment. The present study aims to elucidate the molecular mechanisms underlying Ang II receptor inhibitor LCZ696 treatment in PAH. Initially, a PAH mouse model was induced, followed by intraperitoneal injection of LCZ696. Subsequently, cardiomyocytes and fibroblasts were isolated, cultured, and treated with Ang II and LCZ696, followed by detection of the total survival rate, cardiac injury, cardiac fibrosis and apoptosis. Moreover, in order to quantify the cardiac hypertrophy and fibrosis degree of cardiac fibroblasts, the expression levels of markers of cardiac hypertrophy (ANP, βMHC and TIMP2) and markers of fibrosis (collagen I, collagen III and TGF-β) were evaluated. Furthermore, the potential effect of LCZ696 on the extracellular signal-regulated kinase (ERK) signaling pathway was examined. The acquired findings revealed that LCZ696 increased the total survival rate of PAH mice, but decreased cardiac injury, cardiac fibrosis, and apoptosis in vitro. LCZ696 attenuated cardiac injury induced by Ang II through the inhibition the expression of markers of cardiac hypertrophy, fibrosis and apoptosis by inhibiting ERK phosphorylation in vivo and in vitro. Altogether, LCZ676 could potentially alleviate cardiac remodeling in mice with PAH via blockade of the ERK signaling pathway activation. Our findings suggest that LCZ696 could be a potential target for PAH therapy.

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