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.

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

Circulation ◽  
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.

scholarly journals Maternal Fructose Intake Exacerbates Cardiac Remodeling in Offspring with Ventricular Pressure Overload

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 3267
Author(s):  
Steve Leu ◽  
Kay L. H. Wu ◽  
Wei-Chia Lee ◽  
You-Lin Tain ◽  
Julie Y. H. Chan
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Expression Levels ◽  
Fructose Intake ◽  
Pregnancy And Lactation ◽  
And Oxidative Stress

Recent studies demonstrated that metabolic syndrome and cardiovascular diseases could be elicited by developmental programming, which is regulated by prenatal nutritional and environmental stress. In this study, we utilized a rat model to examine the effect of excessive maternal fructose intake during pregnancy and lactation on cardiac development and progression of pressure overload-induced cardiac hypertrophy in offspring. Transverse aortic constriction (TAC) was performed on 3-month-old male offspring to induce ventricular pressure overload. Four weeks post-TAC, echocardiographic assessment as well as histopathological and biochemical examinations were performed on the myocardium of the offspring. Echocardiographic and gross examinations showed that heart weight, interventricular septal thickness in diastole (IVD; d), and left ventricular posterior wall thickness in diastole (LVPW; d) were elevated in offspring with TAC and further increased by maternal fructose exposure (MFE). However, the left ventricular ejection function was not significantly affected. Myocardial histopathological examination revealed that the indices of fibrosis and oxidative stress were higher in offspring with MFE and TAC than those in animals receiving either treatment. Molecular examinations on the myocardium demonstrated an MFE-induced upregulation of p38-MAPK signaling. Next generation sequence (NGS) analysis indicated a modulation of the expression levels of several cardiac hypertrophy-associated genes, including GPR22, Myh7, Nppa, P2RX4, and Npy by MFE. Subsequent RT-PCR indicated that MFE regulated the expression levels of genes responsive to cardiac hypertrophy (i.e., Myh-7, ANP) and oxidative stress (i.e., GR, GPx, and NQO-1). In conclusion, MFE during pregnancy and lactation modulated myocardial gene expression, increased oxidative stress, and exacerbated ventricular pressure overload-induced cardiac remodeling in rat offspring.

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 Cytosolic H2O2 mediates hypertrophy, apoptosis, and decreased SERCA activity in mice with chronic hemodynamic overload

2014 ◽  
Vol 306 (10) ◽  
pp. H1453-H1463 ◽  
Author(s):  
Fuzhong Qin ◽  
Deborah A. Siwik ◽  
David R. Pimentel ◽  
Robert J. Morgan ◽  
Andreia Biolo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Transgenic Expression ◽  
Myocardial Oxidative Stress ◽  
Plasmic Reticulum ◽  
Oxidative Modifications ◽  
Hemodynamic Overload

Oxidative stress in the myocardium plays an important role in the pathophysiology of hemodynamic overload. The mechanism by which reactive oxygen species (ROS) in the cardiac myocyte mediate myocardial failure in hemodynamic overload is not known. Accordingly, our goals were to test whether myocyte-specific overexpression of peroxisomal catalase (pCAT) that localizes in the sarcoplasm protects mice from hemodynamic overload-induced failure and prevents oxidation and inhibition of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), an important sarcoplasmic protein. Chronic hemodynamic overload was caused by ascending aortic constriction (AAC) for 12 wk in mice with myocyte-specific transgenic expression of pCAT. AAC caused left ventricular hypertrophy and failure associated with a generalized increase in myocardial oxidative stress and specific oxidative modifications of SERCA at cysteine 674 and tyrosine 294/5. pCAT overexpression ameliorated myocardial hypertrophy and apoptosis, decreased pathological remodeling, and prevented the progression to heart failure. Likewise, pCAT prevented oxidative modifications of SERCA and increased SERCA activity without changing SERCA expression. Thus cardiac myocyte-restricted expression of pCAT effectively ameliorated the structural and functional consequences of chronic hemodynamic overload and increased SERCA activity via a post-translational mechanism, most likely by decreasing inhibitory oxidative modifications. In pressure overload-induced heart failure cardiac myocyte cytosolic ROS play a pivotal role in mediating key pathophysiologic events including hypertrophy, apoptosis, and decreased SERCA activity.

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 The SGLT2i Dapagliflozin Reduces RV Hypertrophy Independent of Changes in RV Pressure Induced by Pulmonary Artery Banding

2021 ◽  
Author(s):  
Kim Connelly ◽  
Ellen Wu ◽  
Aylin Visram ◽  
Mark K. Friedberg ◽  
Sri Nagarjun Batchu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Artery ◽  
Protein Expression ◽  
Right Ventricular ◽  
Sglt2 Inhibitor ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Pulmonary Artery Banding ◽  
Calcium Handling ◽  
Sglt2 Inhibition

Abstract Background— Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class might be similarly efficacious in the treatment and prevention of right heart failure has not been unexplored. Hypothesis: We hypothesized that SGLT2 inhibition would reduce the structural, functional and molecular responses to pressure overload of the right ventricle. Methods: Thirteen-week-old Fischer F344 rats underwent pulmonary artery banding (PAB) or sham surgery prior to being randomized to receive either the SGLT2 inhibitor: dapagliflozin (0.5mg/kg/day) or vehicle by oral gavage. After six weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses. Results: PAB induced features consistent with a compensatory response to increased right ventricular (RV) afterload with elevated mass, end systolic pressure, collagen content and alteration in calcium handling protein expression (all p<0.05 when compared to sham + vehicle). Dapagliflozin reduced RV mass, including both wet and dry weight as well as normalizing the protein expression of SERCA 2A, AMPkinase and LC3I/II ratio expression (all p<0.05). Significance: Dapagliflozin reduces the structural, functional, and molecular manifestations of right ventricular pressure overload. Whether amelioration of these early changes in the RV may ultimately lead to a reduction in RV failure remains to be determined.

scholarly journals Changes of Inflammatory and Oxidative Stress Biomarkers in Dogs with Different Stages of Heart Failure

2020 ◽  
Author(s):  
Camila Peres RUBIO ◽  
Ahmet SARIL ◽  
Meriç KOCATURK ◽  
Ryou TANAKA ◽  
Jorgen KOCH ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Acute Phase Proteins ◽  
Staging System ◽  
Serum Levels ◽  
Left Ventricular ◽  
Oxidative Stress Biomarkers ◽  
Stress Biomarkers ◽  
Anti Oxidant ◽  
And Oxidative Stress

Abstract Background: Heart failure (HF) has been associated with changes in inflammatory and oxidative-stress biomarkers. This study aimed to evaluate the changes of a panel of inflammatory and oxidative stress biomarker in dogs with different stages of HF and its relation with the severity of the disease and the echocardiographic changes. Dogs with HF as a result of myxomatous mitral valve degeneration or dilated cardiomyopathy were included. A total of 29 dogs were classified as stage-A (healthy), B (asymptomatic dogs), C (symptomatic dogs) and D (dogs with end-stage-HF) according to the ACVIM-staging-system. Serum cytokines, and inflammatory and oxidative stress markers were evaluated.Results: KC-like as an inflammatory cytokine was significantly increased in dogs of stage-C (P < 0.01) and -D (P < 0.05) compared with stage-A and -B. Stage-D Dogs showed significantly higher serum CRP and Hp (P < 0.05) but lower serum anti-oxidant capacity (PON1, TEAC, CUPRAC, and thiol) compared to stage-A and -B (P < 0.05). After the treatment, serum levels of CRP, Hp and KC-like decreased but serum anti-oxidant levels increased compared to their pre-treatment values. Left ventricular dimension and LA/Ao ratio correlated positively with CRP, MCP-1, and KC-like but negatively with PON1, GM-CSF, IL-7 and antioxidant biomarkers (P < 0.01).Conclusion: our results indicated that dogs with advanced-stages of HF show increases in positive acute-phase proteins and selected inflammatory cytokines (KC-like), and decreases in antioxidant biomarkers, indicating that inflammation and oxidative-stress act as collaborative partners in the pathogenesis of HF. KC-like may be a more useful parameter to monitor disease progression and treatment efficacy of dogs with severe-HF.

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