Endothelin-1 upregulation mediates aging-related cardiac fibrosis

Wang, Xianwei; Guo, Zhikun; Ding, Zufeng; Khaidakov, Magomed; Lin, Juntang; Xu, Zhenping; Sharma, Smriti; Jiwani, Shahanawaz; Mehta, Jawahar L.

doi:10.1016/j.yjmcc.2015.01.001

Cited by 58 publications

(42 citation statements)

References 30 publications

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“…42 In addition, activation of several distinct molecular pathways facilitating production of reactive oxygen species, chemokine-mediated recruitment of mononuclear cells and fibroblast progenitors and utilising TGF-β activation, endothelin-1 and Ang II signalling cascades mediate interstitial and perivascular fibrosis in the senescent heart. 42,43 The therapeutic effect of liraglutide in attenuating age-induced cardiac fibrosis is likely to be mediated via modulation of several aspects of the molecular pathogenesis of this condition including potential effects on reactive oxygen species and chemokine production ( Figures 6-8), as demonstrated in our Ang II hypertension model of cardiac fibrosis, and conceivably involving, as previously mentioned, modulation of Nr4A1 expression.…”

Section: Discussionmentioning

confidence: 63%

Molecular and cellular mechanisms of glucagon-like peptide-1 receptor agonist-mediated attenuation of cardiac fibrosis

Gaspari

Brdar

Lee

et al. 2015

Diabetes and Vascular Disease Research

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Background: Glucagon-like peptide-1 receptor agonists may have a role in modulation of cardiac fibrosis. Our study aimed to determine the effect of the glucagon-like peptide-1 receptor agonist liraglutide in obesity, hypertension and age-induced murine models of cardiac fibrosis and identify associated molecular mechanisms. Methods: C57Bl/6J mice on a high-fat diet and C57Bl/6J mice on a normal chow diet treated with angiotensin II were used to induce obesity and hypertension-mediated cardiac fibrosis, respectively. C57Bl/6J mice 20 months old were used to study age-induced cardiac fibrosis. Liraglutide treatment of 30 µg/kg/day-300 µg/kg s.c. twice daily was administered for 4 weeks. Results: Liraglutide treatment attenuated obesity, hypertension and age-induced increases in interstitial cardiac fibrosis and expression of inflammatory and oxidative stress markers. Conclusions: These observations identify a potential role for liraglutide in the prevention of cardiac fibrosis and identify molecular mechanisms associated with these effects.

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Section: Discussionmentioning

confidence: 63%

Molecular and cellular mechanisms of glucagon-like peptide-1 receptor agonist-mediated attenuation of cardiac fibrosis

Gaspari

Brdar

Lee

et al. 2015

Diabetes and Vascular Disease Research

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“…The up-regulation of the RAAS system in frail patients, as mentioned earlier, mediates an up-regulation of endothelin-1, which in turn mediates an increase in cardiac ibrosis [55]. Cardiac ibrosis, in turn, increases the likelihood of AF by disrupting the cardiac neuroconduction pathways [23].…”

Section: Frailty and Atrial Ibrillation (Af)mentioning

confidence: 87%

Frailty and Cardiovascular Disease

Chainani¹,

Riehl²,

Chainani³

et al. 2017

Frailty and Sarcopenia - Onset, Development and Clinical Challenges

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Cardiovascular disease (CVD) comprises a vast spectrum of disease states ranging from hypertension (HTN) to valvular heart disease (VHD). CVD is known to be the leading cause of morbidity, mortality, and health-care expenditure throughout the world. According to the World Health Organization, coronary artery disease (CAD) and stroke, both subsets of CVD, are the world's biggest killers, accounting for a combined 15 million deaths in 2015. These diseases have remained the leading causes of death globally in the last 15 years. In 2010, CAD alone was projected to cost the U.S. $108.9 billion including the cost of health-care services, medications, and lost productivity. The presence of frailty signiicantly worsens outcomes for patients sufering from CAD. With just this one example of how frailty afects CVD, it is clear that understanding the impact of frailty upon patients alicted with the spectrum of cardiovascular disease is integral for the care of this very signiicant patient population.

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“…In the presence of GPER, increased ECE-2 expression is likely to contribute to augmented local synthesis of ET-1. Thus, GPER may facilitate the activation of the cardiac endothelin system with aging [5-7,10]. Furthermore, GPER-dependent regulation of ET B receptor expression suggests functional cross-talk between the two GPCRs.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, GPER-dependent regulation of ET B receptor expression suggests functional cross-talk between the two GPCRs. Since increased activity of the cardiac endothelin system has been implicated in the progression of heart failure with aging [5-7,10], inhibiting GPER may provide a new approach to reduce myocardial ECE-2 and ET B receptor expression and thus increased ET-1 activity.…”

Section: Discussionmentioning

confidence: 99%

“…In rodents, age-dependent cardiac hypertrophy and fibrosis have been associated with increased myocardial expression of the multifunctional peptide endothelin-1 (ET-1) [5-7], which can induce cardiomyocyte growth and collagen synthesis in cardiac fibroblasts [8,9]. Similarly, aging is associated with increased cardiac expression of endothelin ET A and ET B receptors [6,10], whereas cardiomyocyte hypertrophy and myocardial fibrosis are attenuated in aged mice with cardiomyocyte-specific deletion of the ET A receptor gene [6].…”

Section: Introductionmentioning

confidence: 99%

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GPER is required for the age-dependent upregulation of the myocardial endothelin system

et al. 2016

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Aims Cardiac aging is associated with progressive structural changes and functional impairment, such as left ventricular hypertrophy, fibrosis and diastolic dysfunction. Aging also increases myocardial activity of endothelin-1 (ET-1), a multifunctional peptide with growth-promoting and pro-fibrotic activity. Because the G protein-coupled estrogen receptor (GPER) regulates vascular responsiveness to ET-1, we investigated whether GPER also plays a role in the regulation of the cardiac endothelin system with aging. Main methods Young (4 month-old) and aged (24 month-old) wild-type and Gper-deficient (Gper-/-) mice were studied. Gene expression levels of prepro-ET-1, endothelin converting enzymes ECE-1 and ECE-2, and endothelin ETA and ETB receptors were determined by qPCR in left ventricular myocardium. Key findings Aging markedly increased steady-state mRNA expression levels of ECE-1, ECE-2, ETA and ETB receptors (each p<0.001 vs. young mice). Deletion of Gper inhibited the age-dependent increase in ECE-2 and ETB receptor mRNA levels (57% and 40% reduction, respectively, each p<0.01 vs. wild-type mice), whereas gene expression of prepro-ET-1, ECE-1, or the ETA receptor was unaffected in Gper-/- mice. Significance We identified a novel regulatory mechanism through which the endogenous Gper facilitates the age-dependent increase in myocardial expression of ECE-2 and the ETB receptor, which is compatible with an activating role of GPER for the cardiac endothelin system with aging. Targeting GPER signaling by selective antagonists may therefore be considered a new therapeutic approach to reduce age-dependent increased ET-1 activity and the associated development of left ventricular hypertrophy, fibrosis and heart failure.

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Endothelin-1 upregulation mediates aging-related cardiac fibrosis

Cited by 58 publications

References 30 publications

Molecular and cellular mechanisms of glucagon-like peptide-1 receptor agonist-mediated attenuation of cardiac fibrosis

Molecular and cellular mechanisms of glucagon-like peptide-1 receptor agonist-mediated attenuation of cardiac fibrosis

Frailty and Cardiovascular Disease

GPER is required for the age-dependent upregulation of the myocardial endothelin system

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