An autocrine role for leptin in mediating the cardiomyocyte hypertrophic effects of angiotensin II and endothelin-1

Rajapurohitam, Venkatesh; Javadov, Sabzali; Purdham, Daniel M.; Kirshenbaum, Lorrie A.; Karmazyn, Morris

doi:10.1016/j.yjmcc.2006.05.001

Cited by 91 publications

(78 citation statements)

References 41 publications

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“…To induce hypertrophy, cells were stimulated by angiotensin II (AngII, 1 M) for 36 h in serum-free culture medium (32,33). Cell surface area was analyzed using a Leica inverted microscope equipped with a Polaroid digital camera at ϫ200 magnification.…”

Section: Methodsmentioning

confidence: 99%

Down-regulation of miR-1/miR-133 Contributes to Re-expression of Pacemaker Channel Genes HCN2 and HCN4 in Hypertrophic Heart*

Luo

Lin

Pan

et al. 2008

Journal of Biological Chemistry

166

124

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Cardiac hypertrophy is characterized by electrical remolding with increased risk of arrhythmogenesis. Enhanced abnormal automaticity of ventricular cells contributes critically to hypertrophic arrhythmias. The pacemaker current I f , carried by the hyperpolarization-activated channels encoded mainly by the HCN2 and HCN4 genes in the heart, plays an important role in determining cardiac automaticity. Their expressions reportedly increase in hypertrophic and failing hearts, contributing to arrhythmogenesis under these conditions. We performed a study on post-transcriptional regulation of expression of HCN2 and HCN4 genes by microRNAs. We experimentally established HCN2 as a target for repression by the muscle-specific microRNAs miR-1 and miR-133 and established HCN4 as a target for miR-1 only. We unraveled robust increases in HCN2 and HCN4 protein levels in a rat model of left ventricular hypertrophy and in angiotensin II-induced neonatal ventricular hypertrophy. The up-regulation of HCN2/HCN4 was accompanied by pronounced reduction of miR-1/miR-133 levels. Forced expression of miR-1/miR-133 by transfection prevented overexpression of HCN2/HCN4 in hypertrophic cardiomyocytes. The serum-responsive factor protein level was found significantly decreased in hypertrophic hearts, and silencing of this protein by RNA interference resulted in increased levels of miR-1/miR-133 and concomitant increases in HCN2 and HCN4 protein levels. We conclude that down-regulation of miR-1 and miR-133 expression contributes to re-expression of HCN2/HCN4 and thereby the electrical remodeling process in hypertrophic hearts. Our study also sheds new light on the cellular function and pathological role of miR-1/miR-133 in the heart.

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Section: Methodsmentioning

confidence: 99%

Down-regulation of miR-1/miR-133 Contributes to Re-expression of Pacemaker Channel Genes HCN2 and HCN4 in Hypertrophic Heart*

Luo

Lin

Pan

et al. 2008

Journal of Biological Chemistry

166

124

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“…88 Whether leptin is upstream and/or downstream of ET-1 secretion appears to be controversial. 87,88 Myocardial NHE-1 mRNA abundance was enhanced in right ventricular hypertrophy caused by monocrotaline-induced pulmonary artery injury. Both hypertrophy and NHE-1 upregulation were abrogated by treatment with cariporide.…”

Section: The Nhe-1 In Myocardial Hypertrophymentioning

confidence: 99%

“…86 -88 It has been reported that leptin elevates ET-1 and ROS levels, which results in hypertrophy of neonatal rat cardiac myocytes. 87 Therefore, it seems reasonable to speculate that NHE-1 hyperactivity is involved in this prohypertrophic signaling pathway. More recently, Karmazyn's group 87 implicated leptin as an autocrine mediator of the hypertrophic effects of Ang II and ET-1 in cultured neonatal ventricular myocytes.…”

Section: The Nhe-1 In Myocardial Hypertrophymentioning

confidence: 99%

Sodium-Hydrogen Exchanger, Cardiac Overload, and Myocardial Hypertrophy

2007

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“…21 Its expression is increased by overfeeding, insulin, glucocorticoids, endotoxin, and cytokines and is decreased by fasting, testosterone, thyroid hormone, and exposure to cold temperature. 22,23 In the heart, increased leptin expression is seen following reperfusion after ischemia, 24,25 and leptin concentration in cardiomyocyte culture serum is increased with endothelin (ET)-1 and angiotensin (Ang) II treatment, 26 suggesting the heart as a site of leptin production.…”

Section: Leptin Signaling Leptin and Leptin Receptormentioning

confidence: 99%

Leptin Signaling and Obesity

Yang

Barouch

2007

Circulation Research

281

131

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Abstract-Leptin, among the best known hormone markers for obesity, exerts pleiotropic actions on multiple organ systems. In this review, we summarize major leptin signaling pathways, namely Janus-activated kinase/signal transducers and activators of transcription and mitogen-activated protein kinase, including possible mechanisms of leptin resistance in obesity. The effects of leptin on the cardiovascular system are discussed in detail, including its contributions to hypertension, atherosclerosis, depressed myocardial contractile function, fatty acid metabolism, hypertrophic remodeling, and reduction of ischemic/reperfusion injury. The overall goal is to summarize current understanding of how altered leptin signaling in obesity contributes to obesity-related cardiovascular disease. Extensive evidence now supports the notion that maladaptation of the biological system for weight maintenance makes it extremely difficult for people to maintain weight loss. 1 Several genes have been identified to disclose a physiological system that maintains body weight within a range of about twenty pounds. 2 A key element of this system is leptin, the 16-kDa hormonal product of the obesity (ob) gene. 3 Leptin is primarily secreted by adipocytes and is a classic member of the more than 50 identified adipocytokines that participate in adipose tissue hormonal signaling. 4 Since its identification in 1994, leptin has attracted much attention as one of the most important central and peripheral signals for the maintenance of energy homeostasis. [5][6][7][8] For example, a 9-year-old girl with extreme obesity was found to lack leptin. 9 Leptin treatment reduced her weight to the normal range for her age, and the same effects were observed in her similarly affected cousin. 10 Plasma leptin is generally proportional to adipose mass. 11,12 The primary physiological role of leptin is to communicate to the central nervous system (CNS) the abundance of available energy stores and to restrain food intake and induce energy expenditure. The absence of leptin therefore leads to increased appetite and food intake that result in morbid obesity. Notably, only rare cases of severe early childhood obesity have been associated with leptin deficiency. 9,13 The remainder of the obese population typically have elevated leptin levels. 14 The failure of leptin to induce weight loss in these cases is thought to be the result of leptin resistance.Hyperleptinemia, nearly universally observed in human obesity and animal models, is accompanied by a disruption of the usual activities of the hormone, possibly at different Original received May 22, 2007; revision received July 20, 2007; accepted August 6, 2007 18 -20 Obesity is also a part of the metabolic syndrome, which is diagnosed by a set of criteria that include abdominal obesity, insulin resistance, dyslipidemia, and hypertension. This patient population faces increased risk for type 2 diabetes and cardiovascular diseases. The widely distributed Ob-Rs make the hormone an attractive candidate for a molecul...

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An autocrine role for leptin in mediating the cardiomyocyte hypertrophic effects of angiotensin II and endothelin-1

Cited by 91 publications

References 41 publications

Down-regulation of miR-1/miR-133 Contributes to Re-expression of Pacemaker Channel Genes HCN2 and HCN4 in Hypertrophic Heart*

Down-regulation of miR-1/miR-133 Contributes to Re-expression of Pacemaker Channel Genes HCN2 and HCN4 in Hypertrophic Heart*

Sodium-Hydrogen Exchanger, Cardiac Overload, and Myocardial Hypertrophy

Leptin Signaling and Obesity

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