Leptin and Vascular Smooth Muscle

Zeidan, Asad; Karmazyn, Morris

doi:10.2174/157016106778521634

Cited by 10 publications

(4 citation statements)

References 109 publications

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“…It is secreted by adipocytes and binds to the hypothalamic leptin receptor (Ob-R) to enhance metabolism and reduce appetite [ 4 ], thereby increasing energy expenditure and decreasing energy intake. It is a product of the ob gene [ 5 ] and is associated with obesity, since a higher adipose tissue mass results in elevated leptin levels [ 6 ].…”

Section: Leptinmentioning

confidence: 99%

“…Several studies have shown that the functional leptin receptor is also found in a variety of organs such as the heart, liver, kidneys, and pancreas [ 9 – 13 ]. It is located on cardiomyocytes [ 14 ], vascular smooth muscle cells [ 5 ], endothelial cells [ 15 ], myometrium [ 16 ], and cerebral and coronary vessels [ 17 , 18 ]. Therefore, this hormone has a wide range of pleiotropic effects, affecting the cardiovascular, nervous, immune, and reproductive systems [ 19 – 21 ].…”

Section: Leptinmentioning

confidence: 99%

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Differential Role of Leptin and Adiponectin in Cardiovascular System

Ghantous

Azrak

Hanache

et al. 2015

International Journal of Endocrinology

176

119

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Leptin and adiponectin are differentially expressed adipokines in obesity and cardiovascular diseases. Leptin levels are directly associated with adipose tissue mass, while adiponectin levels are downregulated in obesity. Although significantly produced by adipocytes, leptin is also produced by vascular smooth muscle cells and cardiomyocytes. Plasma leptin concentrations are elevated in cases of cardiovascular diseases, such as hypertension, congestive heart failure, and myocardial infarction. As for the event of left ventricular hypertrophy, researchers have been stirring controversy about the role of leptin in this form of cardiac remodeling. In this review, we discuss how leptin has been shown to play an antihypertrophic role in the development of left ventricular hypertrophy through in vitro experiments, population-based cross-sectional studies, and longitudinal cohort studies. Conversely, we also examine how leptin may actually promote left ventricular hypertrophy using in vitro analysis and human-based univariate and multiple linear stepwise regression analysis. On the other hand, as opposed to leptin's generally detrimental effects on the cardiovascular system, adiponectin is a cardioprotective hormone that reduces left ventricular and vascular hypertrophy, oxidative stress, and inflammation. In this review, we also highlight adiponectin signaling and its protective actions on the cardiovascular system.

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Section: Leptinmentioning

confidence: 99%

Section: Leptinmentioning

confidence: 99%

Differential Role of Leptin and Adiponectin in Cardiovascular System

Ghantous

Azrak

Hanache

et al. 2015

International Journal of Endocrinology

176

119

View full text Add to dashboard Cite

show abstract

“…Leptin is a 16 kDa protein that is the product of the ob gene (Zeidan and Karmazyn, 2006 ) and found in excessive levels in obesity (Sinha et al, 1996 ). It reduces appetite and increases energy expenditure, but also found to exert pleiotropic effects on several physiological systems, such as the nervous, immune, reproductive, and cardiovascular systems (Zeidan et al, 2006 ; Karmazyn et al, 2008 ; Fernández-Riejos et al, 2010 ; Zuure et al, 2013 ; Procaccini et al, 2014 ; reviewed by Ghantous et al, 2015a ).…”

Section: Introductionmentioning

confidence: 99%

Calcineurin/NFAT Activation-Dependence of Leptin Synthesis and Vascular Growth in Response to Mechanical Stretch

et al. 2016

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Background and Aims: Hypertension and obesity are important risk factors of cardiovascular disease. They are both associated with high leptin levels and have been shown to promote vascular hypertrophy, through the RhoA/ROCK and ERK1/2 phosphorylation. Calcineurin/NFAT activation also induces vascular hypertrophy by upregulating various genes. This study aimed to decipher whether a crosstalk exists between the RhoA/ROCK pathway, Ca2+/calcineurin/NFAT pathway, and ERK1/2 phosphorylation in the process of mechanical stretch-induced vascular smooth muscle cell (VSMC) hypertrophy and leptin synthesis.Methods and Results: Rat portal vein (RPV) organ culture was used to investigate the effect of mechanical stretch and exogenous leptin (3.1 nM) on VSMC hypertrophy and leptin synthesis. Results showed that stretching the RPV significantly upregulated leptin secretion, mRNA, and protein expression, which were inhibited by the calcium channel blocker nifedipine (10 μM), the selective calcineurin inhibitor FK506 (1 nM), and the ERK1/2 inhibitor PD98059 (1 μM). The transcription inhibitor actinomycin D (0.1 μM) and the translation inhibitor cycloheximide (1 mM) significantly decreased stretch-induced leptin protein expression. Mechanical stretch or leptin caused an increase in wet weight changes and protein synthesis, considered as hypertrophic markers, while they were inhibited by FK506 (0.1 nM; 1 nM). In addition, stretch or exogenous leptin significantly increased calcineurin activity and MCIP1 expression whereas leptin induced NFAT nuclear translocation in VSMCs. Moreover, in response to stretch or exogenous leptin, the Rho inhibitor C3 exoenzyme (30 ng/mL), the ROCK inhibitor Y-27632 (10 μM), and the actin depolymerization agents Latrunculin B (50 nM) and cytochalasin D (1 μM) reduced calcineurin activation and NFAT nuclear translocation. ERK1/2 phosphorylation was inhibited by FK506 and C3.Conclusions: Mechanical stretch-induced VSMC hypertrophy and leptin synthesis and secretion are mediated by Ca2+/calcineurin/NFAT activation. RhoA/ROCK and ERK1/2 activation are critical for mechanical stretch-induced calcineurin activation.

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“…In addition to adipocytes, leptin is produced by other kinds of cells including cardiomyocytes and VSMCs ( Zeidan et al, 2005 ; Matsui et al, 2007 ). Different studies have shown that the functional leptin receptor, leptin receptor b (OBRb), is found in a variety of cells such as VSMCs ( Zeidan et al, 2005 ; Zeidan and Karmazyn, 2006 ), cardiomyocytes ( Rajapurohitam et al, 2003 ), myometrial cells ( Markowska et al, 2005 ), endothelial cells ( Mutze et al, 2006 ), and T-lymphocytic cells ( Martin-Romero et al, 2000 ; Lord et al, 2002 ). Therefore, this hormone has a wide range of pleiotropic effects and affects the cardiovascular, nervous, reproductive, and immune systems ( Lord et al, 1998 ; Margetic et al, 2002 ; Rahmouni and Haynes, 2004 ).…”

Section: Introductionmentioning

confidence: 99%

Mechanical stretch-induced vascular hypertrophy occurs through modulation of leptin synthesis-mediated ROS formation and GATA-4 nuclear translocation

et al. 2015

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Background: Obesity and hypertension are associated with increased leptin production contributing to cardiovascular remodeling. Mechanisms involving mechanical stretch-induced leptin production and the cross talk between signaling pathways leading to vascular remodeling have not been fully elucidated.Methods and Results: Rat portal vein (RPV) organ culture was used to investigate the effect of mechanical stretch on leptin protein expression in vascular smooth muscle cells (VSMCs). Moreover, the involvement of reactive oxygen species (ROS), the RhoA/ROCK pathway, actin cytoskeleton dynamics and the transcriptional factor GATA-4 activation in mechanical stretch-induced vascular remodeling were investigated. Stretching the RPV for 1 or 24 h significantly increased leptin protein level and ROS formation in VSMCs, which was prevented by 1 h pretreatment with the ROCK inhibitor Y-27632 and the actin cytoskeleton depolymerization agent cytochalasin D. Moreover, Western blotting and immunohistochemistry revealed that mechanical stretch or treatment with 3.1 nmol/L leptin for 24 h significantly increased actin polymerization, as reflected by an increase in the F-actin to G-actin ratio. Increases in blood vessels’ wet weight and [3H]-leucine incorporation following a 24 h treatment with conditioned media from cultured stretched RPVs indicated RPV hypertrophy. This effect was prevented by 1 h pretreatment with anti-leptin antibody, indicating leptin’s crucial role in promoting VSMC hypertrophy. As an index of GATA-4 activation, GATA-4 nuclear translocation was assessed by immunohistochemistry method. Pretreating VSMC with leptin for 1 h significantly activated GATA-4 nuclear translocation, which was potently attenuated by the NADPH oxidase inhibitor apocynin, Y-27632, and cytochalasin D.Conclusion: Our results demonstrate that ROS formation, RhoA/ROCK pathway, and GATA-4 activation play a pivotal role in mechanical stretch-induced leptin synthesis leading to VSMC remodeling.

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Leptin and Vascular Smooth Muscle

Cited by 10 publications

References 109 publications

Differential Role of Leptin and Adiponectin in Cardiovascular System

Differential Role of Leptin and Adiponectin in Cardiovascular System

Calcineurin/NFAT Activation-Dependence of Leptin Synthesis and Vascular Growth in Response to Mechanical Stretch

Mechanical stretch-induced vascular hypertrophy occurs through modulation of leptin synthesis-mediated ROS formation and GATA-4 nuclear translocation

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