Role of serotonin 5-HT2A receptors in the development of cardiac hypertrophy in response to aortic constriction in mice

2013 ◽  
Vol 120 (6) ◽  
pp. 927-935 ◽  
Author(s):  
O. Lairez ◽  
T. Cognet ◽  
S. Schaak ◽  
D. Calise ◽  
C. Guilbeau-Frugier ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Aortic Constriction

THE ROLE OF GROWTH HORMONE AND THYROXINE IN NEPHROGENIC HYPERTENSION AND CARDIAC HYPERTROPHY IN HYPOPHYSECTOMIZED RATS

1967 ◽  
Vol 45 (6) ◽  
pp. 993-1000 ◽  
Author(s):  
Margaret Beznak
Keyword(s):  
Blood Pressure ◽  
Growth Hormone ◽  
Cardiac Hypertrophy ◽  
Male Rats ◽  
Unilateral Nephrectomy ◽  
Aortic Constriction ◽  
Salt Loading ◽  
Hypophysectomized Rats

There was no indication of slowly developing hypertension and cardiac hypertrophy in hypophysectomized rats upon treatment with desoxycorticosterone and salt loading following unilateral nephrectomy. This was the case in both younger (less than 100 g) and older (220–260 g) male rats. However, the weight of the heart and kidney, the blood pressure, and the rate and output of the heart of normal and hypophysectomized rats following unilateral nephrectomy and treatment with desoxycorticosterone and salt loading were not too different when the hypophysectomized rats were given growth hormone and thyroxine. This agrees with the earlier conclusion that thyroxine and growth hormone are required in hypophysectomized rats for the development of hypertension and any significant enlargement of the heart, whether from aortic constriction or from nephrogenic causes.

scholarly journals Myeloid MKL1 Disseminates Cues to Promote Cardiac Hypertrophy in Mice

2021 ◽  
Vol 9 ◽  
Author(s):  
Li Liu ◽  
Qianwen Zhao ◽  
Lin Lin ◽  
Guang Yang ◽  
Liming Yu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cell Types ◽  
Conditional Knockout ◽  
Dependent Manner ◽  
Aortic Constriction ◽  
Hypertrophic Response ◽  
Cardiac Inflammation ◽  
Pathological Hypertrophy ◽  
Response To Stress

Cardiac hypertrophy is a key pathophysiological process in the heart in response to stress cues. Although taking place in cardiomyocytes, the hypertrophic response is influenced by other cell types, both within the heart and derived from circulation. In the present study we investigated the myeloid-specific role of megakaryocytic leukemia 1 (MKL1) in cardiac hypertrophy. Following transverse aortic constriction (TAC), myeloid MKL1 conditional knockout (MFCKO) mice exhibit an attenuated phenotype of cardiac hypertrophy compared to the WT mice. In accordance, the MFCKO mice were protected from excessive cardiac inflammation and fibrosis as opposed to the WT mice. Conditioned media collected from macrophages enhanced the pro-hypertrophic response in cardiomyocytes exposed to endothelin in an MKL1-dependent manner. Of interest, expression levels of macrophage derived miR-155, known to promote cardiac hypertrophy, were down-regulated in the MFCKO mice compared to the WT mice. MKL1 depletion or inhibition repressed miR-155 expression in macrophages. Mechanistically, MKL1 interacted with NF-κB to activate miR-155 transcription in macrophages. In conclusion, our data suggest that MKL1 may contribute to pathological hypertrophy via regulating macrophage-derived miR-155 transcription.

scholarly journals miR-139-5p inhibits isoproterenol-induced cardiac hypertrophy by targetting c-Jun

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Su Ming ◽  
Wang Shui-yun ◽  
Qiu Wei ◽  
Li Jian-hui ◽  
Hui Ru-tai ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Monogenic Disease ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Rat Cardiomyocytes ◽  
Neonatal Rat Cardiomyocytes ◽  
Regulatory Effects

Hypertrophic cardiomyopathy (HCM) is a serious monogenic disease characterized by cardiac hypertrophy, fibrosis, sudden cardiac death, and heart failure. Previously, we identified that miR-139-5p was down-regulated in HCM patients. However, the regulatory effects of miR-139-5p remain unclear. Thus, we investigated the role of miR-139-5p in the regulation of cardiac hypertrophy. The expression of miR-139-5p in left ventricular tissues in HCM patients and mice subjected to transverse aortic constriction (TAC) was significantly down-regulated. Knockdown of miR-139-5p expression in neonatal rat cardiomyocytes (NRCMs) induced cardiomyocyte enlargement and increased atrial natriuretic polypeptide (ANP) expression. Overexpression of miR-139-5p antagonized isoproterenol (ISO)-induced cardiomyocyte enlargement and ANP/brain natriuretic peptide (BNP) up-regulation. More importantly, we found that c-Jun expression was inhibited by miR-139-5p in NRCMs. Knockdown of c-Jun expression significantly attenuated cardiac hypertrophy induced by miR-139-5p deprivation. Our data indicated that miR-139-5p was down-regulated in the hearts of HCM patients and that it inhibited cardiac hypertrophy by targetting c-Jun expression.

scholarly journals Deubiquitinase Inhibitor Auranofin Attenuated Cardiac Hypertrophy by Blocking NF-κB Activation

2018 ◽  
Vol 45 (6) ◽  
pp. 2421-2430 ◽  
Author(s):  
Ming Hu ◽  
Zhenhui Zhang ◽  
Bin Liu ◽  
Shuangwei Zhang ◽  
Renjie Chai ◽  
...  
Keyword(s):  
Left Ventricular Hypertrophy ◽  
Cardiac Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Myocardial Cell ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Aortic Constriction ◽  
Cell Hypertrophy ◽  
Abdominal Aortic

Background/Aims: Cardiac hypertrophy is a major outcome and compensatory response of the cardiovascular system to hemodynamic and additional stress responses that ultimately lead to heart failure. Auranofin (Aur) has been used for treating rheumatic arthritis for several decades. Aur is a 19S proteasome-associated deubiquitinase inhibitor, and inhibition of the proteasome is speculated to reverse cardiac hypertrophy. However, the role of the deubiquitinases, especially 19S proteasome-associated deubiquitinases, in the regulation of cardiac remodeling remains poorly understood. The present study investigated the role of Aur in cardiac hypertrophy both in vitro and in vivo. Methods: Male Sprague–Dawley rats underwent abdominal aortic constriction to induce left ventricular hypertrophy. The neonatal rat primary myocardial cell hypertrophy model was induced by Ang II. Echocardiography, hematoxylin-eosin staining, Masson’s trichrome staining, immunochemistry, western blot analysis, a cell viability assay, and enzyme-linked immunosorbent assay were performed. Results: Aur significantly reduced the abdominal aortic constriction that led to left ventricular hypertrophy, reduced heart cavity expansion, and functional disorder, and thereby reduced fetal gene expression and attenuated cardiac fibrosis. Furthermore, Aur caused marked accumulation of ubiquitinated proteins and IκBα, as well as inactivation of NF-κB. This phenomenon was confirmed in the neonatal rat primary myocardial cell hypertrophy model. Conclusions: The present study indicated that Aur blocks the development of left ventricular hypertrophy induced by abdominal aortic constriction. This phenomenon might be attributed to inhibition of the 19S proteasome-associated deubiquitinase that can lead to aggregation of IκBα and inactivation of the NF-κB pathway. Thus, Aur could be a potential anti-cardiac hypertrophy agent.

scholarly journals A disintegrin and metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis

2020 ◽  
Vol 318 (2) ◽  
pp. H238-H251 ◽  
Author(s):  
Yuto Nakamura ◽  
Shunbun Kita ◽  
Yoshimitsu Tanaka ◽  
Shiro Fukuda ◽  
Yoshinari Obata ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Focal Adhesion ◽  
Cardiac Dysfunction ◽  
Transverse Aortic Constriction ◽  
Wild Type ◽  
Aortic Constriction ◽  
A Disintegrin And Metalloproteinase ◽  
Adam 12

A disintegrin and metalloproteinase (ADAM)12 is considered to promote cardiac dysfunction based on the finding that a small-molecule ADAM12 inhibitor, KB-R7785, ameliorated cardiac function in a transverse aortic constriction (TAC) model by inhibiting the proteolytic activation of heparin-binding-EGF signaling. However, this compound has poor selectivity for ADAM12, and the role of ADAM12 in cardiac dysfunction has not yet been investigated using genetic loss-of-function mice. We revealed that ADAM12 knockout mice showed significantly more advanced cardiac hypertrophy and higher mortality rates than wild-type mice 4 wk after TAC surgery. An ADAM12 deficiency resulted in significantly more expanded cardiac fibrosis accompanied by increased collagen-related gene expression in failing hearts. The results of a genome-wide transcriptional analysis suggested a strongly enhanced focal adhesion- and fibrosis-related signaling pathway in ADAM12 knockout hearts. The loss of ADAM12 increased the abundance of the integrinβ1 subunit and transforming growth factor (TGF)-β receptor types I and III, and this was followed by the phosphorylation of focal adhesion kinase, Akt, mammalian target of rapamycin, ERK, and Smad2/3 in the heart, which resulted in cardiac dysfunction. The present results revealed that the loss of ADAM12 enhanced focal adhesion and canonical TGF-β signaling by regulating the abundance of the integrinβ1 and TGF-β receptors. NEW & NOTEWORTHY In contrast to a long-believed cardio-damaging role of a disintegrin and metalloproteinase (ADAM)12, cardiac hypertrophy was more severe, cardiac function was lower, and mortality was higher in ADAM12 knockout mice than in wild-type mice after transverse aortic constriction surgery. The loss of ADAM12 enhanced focal adhesion- and fibrosis-related signaling pathways in the heart, which may compromise cardiac function. These results provide insights for the development of novel therapeutics that target ADAM12 to treat heart failure.

scholarly journals NLRP3-mediated pyroptosis aggravates pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction in mice: cardioprotective role of irisin

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Rongchuan Yue ◽  
Zaiyong Zheng ◽  
Yu Luo ◽  
Xiaobo Wang ◽  
Mingming Lv ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Nlrp3 Inflammasome ◽  
Critical Role ◽  
Pressure Overload ◽  
Receptor Protein ◽  
Therapeutic Effects ◽  
Aortic Constriction ◽  
Cardioprotective Effects ◽  
Promising Therapeutic Agent

AbstractThe exact mechanism of myocardial hypertrophy has not been completely elucidated. NOD-like receptor protein 3 (NLRP3) and the pyroptotic cascade play a critical role in cardiac hypertrophy and inflammation. The myokine irisin can inhibit NLRP3 activation, although its exact mechanism of action is unknown. In this study, we induced cardiac hypertrophy in a mouse model via aortic constriction (TAC) to further explore the pathological role of NLRP3 inflammasome-mediated pyroptosis and the potential therapeutic effects of irisin. Cardiac hypertrophy significantly increased the percentage of apoptotic cells and upregulated IL-1β, cleaved caspase-1, and GSDMD-N that lie downstream of the NLRP3 inflammasome. Subsequently, irisin was co-administered to the TAC mice or angiotensin II (Ang-II)-treated cardiomyocytes to observe whether it could attenuate pyroptosis and cardiac hypertrophy. We established a direct association between pyroptosis and cardiac hypertrophy and found that pharmacological or genetic inhibition of NLRP3 attenuated cardiac hypertrophy. Furthermore, ectopic overexpression of NLRP3 abrogated the cardioprotective effects of irisin. To summarize, pyroptosis is a pathological factor in cardiac hypertrophy, and irisin is a promising therapeutic agent that inhibits NLRP3-mediated pyroptosis of cardiomyocytes.

Ameliorative role of gemfibrozil against partial abdominal aortic constriction-induced cardiac hypertrophy in rats

2014 ◽  
Vol 25 (4) ◽  
pp. 725-730 ◽  
Author(s):  
Amrit Pal Singh ◽  
Randhir Singh ◽  
Pawan Krishan
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Left Ventricular ◽  
High Density Lipoproteins ◽  
Peroxisome Proliferator ◽  
Aortic Constriction ◽  
Abdominal Aortic ◽  
Significant Change

AbstractFibrates are peroxisome proliferator-activated receptor-α agonists and are clinically used for treatment of dyslipidemia and hypertriglyceridemia. Fenofibrate is reported as a cardioprotective agent in various models of cardiac dysfunction; however, limited literature is available regarding the role of gemfibrozil as a possible cardioprotective agent, especially in a non-obese model of cardiac remodelling. The present study investigated the role of gemfibrozil against partial abdominal aortic constriction-induced cardiac hypertrophy in rats. Cardiac hypertrophy was induced by partial abdominal aortic constriction in rats and they survived for 4 weeks. The cardiac hypertrophy was assessed by measuring left ventricular weight to body weight ratio, left ventricular wall thickness, and protein and collagen content. The oxidative stress in the cardiac tissues was assessed by measuring thiobarbituric acid-reactive substances, superoxide anion generation, and reduced glutathione level. The haematoxylin–eosin and picrosirius red staining was used to observe cardiomyocyte diameter and collagen deposition, respectively. Moreover, serum levels of cholesterol, high-density lipoproteins, triglycerides, and glucose were also measured. Gemfibrozil (30 mg/kg, p.o.) was administered since the first day of partial abdominal aortic constriction and continued for 4 weeks. The partial abdominal aortic constriction-induced cardiac oxidative stress and hypertrophy are indicated by significant change in various parameters used in the present study that were ameliorated with gemfibrozil treatment in rats. No significant change in serum parameters was observed between various groups used in the present study. It is concluded that gemfibrozil ameliorates partial abdominal aortic constriction-induced cardiac oxidative stress and hypertrophy and in rats.

scholarly journals A CRITICAL ROLE OF TRPC1-ORAI1-STIM1 MEDIATED STORE OPERATED CALCIUM ENTRY IN CARDIAC HYPERTROPHY

2015 ◽  
Vol 65 (10) ◽  
pp. A902
Author(s):  
Senthil Selvaraj ◽  
Brij Singh ◽  
Christian Bollensdorff ◽  
Jassim Al Suwaidi ◽  
Magdi Yacoub
Keyword(s):  
Cardiac Hypertrophy ◽  
Critical Role ◽  
Calcium Entry ◽  
Store Operated Calcium Entry

Inhibition of the water channel aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V Montiel ◽  
R Bella ◽  
L Michel ◽  
E Robinson ◽  
J.C Jonas ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Cardiac Hypertrophy ◽  
Cardiac Myocytes ◽  
Cardiac Remodeling ◽  
Cardiac Myocyte ◽  
Water Channel ◽  
Transmembrane Transport ◽  
Funding Source ◽  
Water Pore

Abstract Background Pathological remodeling of the myocardium has long been known to involve oxidant signaling, but so far, strategies using systemic anti-oxidants have generally failed to prevent it. Aquaporins are a family of transmembrane water channels with thirteen isoforms currently known. Some isoforms have been implicated in oxidant signaling. AQP1 is the most abundant aquaporin in cardiovascular tissues but its specific role in cardiac remodeling remains unknown. Purpose We tested the role of AQP1 as a key regulator of oxidant-mediated cardiac remodeling amenable to targeted pharmacological therapy. Methods We used mice with genetic deletion of Aqp1 (and wild-type littermate), as well as primary isolates from the same mice and human iPSC/Engineered Heart Tissue to test the role of AQP1 in pro-hypertrophic signaling. Human cardiac myocyte-specific (PCM1+) expression of AQP's and genes involved in hypertrophic remodeling was studied by RNAseq and bioinformatic GO pathway analysis. Results RNA sequencing from human cardiac myocytes revealed that the archetypal AQP1 is a major isoform. AQP1 expression correlates with the severity of hypertrophic remodeling in patients with aortic stenosis. The AQP1 channel was detected at the plasma membrane of human and mouse cardiac myocytes from hypertrophic hearts, where it colocalizes with the NADPH oxidase-2 (NOX2) and caveolin-3. We show that hydrogen peroxide (H2O2), produced extracellularly, is necessary for the hypertrophic response of isolated cardiac myocytes and that AQP1 facilitates the transmembrane transport of H2O2 through its water pore, resulting in activation of oxidant-sensitive kinases in cardiac myocytes. Structural analysis of the amino acid residues lining the water pore of AQP1 supports its permeation by H2O2. Deletion of Aqp1 or selective blockade of AQP1 intra-subunit pore (with Bacopaside II) inhibits H2O2 transport in mouse and human cells and rescues the myocyte hypertrophy in human induced pluripotent stem cell-derived engineered heart muscle. This protective effect is due to loss of transmembrane transport of H2O2, but not water, through the intra-subunit pore of AQP1. Treatment of mice with clinically-approved Bacopaside extract (CDRI08) inhibitor of AQP1 attenuates cardiac hypertrophy and fibrosis. Conclusion We provide the first demonstration that AQP1 functions as an aqua-peroxiporin in primary rodent and human cardiac parenchymal cells. We show that cardiac hypertrophy is mediated by the transmembrane transport of H2O2 through the AQP1 water channel. Our studies open the way to complement the therapeutic armamentarium with specific blockers of AQP1 for the prevention of adverse remodeling in many cardiovascular diseases leading to heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): FRS-FNRS, Welbio

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