Peroxisome Proliferator-Activated Receptor-γ Ameliorates Pulmonary Arterial Hypertension by Inhibiting 5-Hydroxytryptamine 2B Receptor

Liu, Bing; Tian, Xiaoyu; Mao, Guangmei; Fang, Xi; Fung, Man Lung; Shyy, John Y.‐J.; Huang, Yü; Wang, Nanping

doi:10.1161/hypertensionaha.112.198887

Cited by 45 publications

(51 citation statements)

References 53 publications

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“…Thus, to cast an even wider net for capturing all genes highly active in reports linking PPARγ directly to PH development (20)(21)(22). However, the full spectrum of the regulation and downstream actions of PPARγ in PH remains undescribed (23).…”

Section: Resultsmentioning

confidence: 99%

Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension

Bertero¹,

Lu²,

Annis³

et al. 2014

J. Clin. Invest.

197

234

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Section: Resultsmentioning

confidence: 99%

Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension

Bertero¹,

Lu²,

Annis³

et al. 2014

J. Clin. Invest.

197

234

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“…Accumulating evidence suggests that serotonin [5-hydroxytryptamine (5-HT)], a well-known mitogen and a potent vasoconstrictor, may also stimulate pathological processes in diabetes (16). 5-HT has been associated with cardiovascular diseases such as atherosclerosis (10) and pulmonary hypertension (14), but it has been overlooked in some diseases because of its low circulating physiological levels (estimated to be in the 10 Ϫ9 M range; Ref. 28) and a lack of understanding of the roles of 5-HT in the peripheral systems.…”

mentioning

confidence: 99%

Molecular interactions of serotonin (5-HT) and endothelin-1 in vascular smooth muscle cells: in vitro and ex vivo analyses

Bhaskaran

Zaluski

Banes-Berceli

2014

American Journal of Physiology-Cell Physiology

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Bhaskaran S, Zaluski J, Banes-Berceli A. Molecular interactions of serotonin (5-HT) and endothelin-1 in vascular smooth muscle cells: in vitro and ex vivo analyses. Am J Physiol Cell Physiol 306: C143-C151, 2014. First published November 6, 2013; doi:10.1152/ajpcell.00247.2013.-Elevated levels of serotonin (5-HT) and endothelin-1 (ET-1) may be involved in cardiovascular complications of diabetes mellitus. Data suggest supraphysiological concentrations of 5-HT (10 Ϫ6 M) potentiate the ability of ET-1 to stimulate DNA synthesis and vascular smooth muscle cell (VSMC) proliferation in vitro via activation of mitogen-activated protein kinase (p42/44 MAPK) and Janus kinase 2 (JAK2) pathways. Additionally, 5-HT enhances agonist-induced contractions via p42/44 MAPK and an unknown tyrosine kinase. However, the exact mechanisms of the 5-HT/ET-1 interactions and whether these effects occur at physiological levels (10 Ϫ9 M) are unknown. Therefore, we hypothesized that interactions between 5-HT and ET-1 at physiological concentrations in VSMC enhanced activation of both p42/44 MAPK and JAK2 pathways contributing to vascular growth and contractile responses. With the use of rat VSMC and Western blot analysis, our data suggest no effect of acute (30 min) preincubation with 5-HT (10 Ϫ9 M) and/or ET-1 (10 Ϫ9 M) on the activation of either pathway in normal or high glucose conditions. To determine if there was altered vascular reactivity in intact vessels we tested the effects of 5-HT and ET-1 interaction using myographs to measure isometric contractions of rat thoracic aortic rings. 5-HT (10 Ϫ9 M) and ET-1 (10 Ϫ12 M) stimulate enhanced contractile responses to each other that were inhibited by JAK2 and p42/44 MAPK antagonists. Our findings demonstrate that both 5-HT and ET-1 at physiological concentrations could interact with each other and activate p42/44 MAPK and JAK2 signaling pathways to cause an increase in smooth muscle contraction that could lead to altered vascular function. diabetes; serotonin (5-HT); endothelin-1 (ET-1); vascular smooth muscle cell (VSMC); p42/44 mitogen-activated protein kinase (p42/44 MAPK); Janus kinase 2 (JAK2) DIABETES MELLITUS IS A LEADING cause of renal disease and an independent risk factor for cardiovascular disease complications in the United States. Accumulating evidence suggests that serotonin [5-hydroxytryptamine (5-HT)], a well-known mitogen and a potent vasoconstrictor, may also stimulate pathological processes in diabetes (16). 5-HT has been associated with cardiovascular diseases such as atherosclerosis (10) and pulmonary hypertension (14), but it has been overlooked in some diseases because of its low circulating physiological levels (estimated to be in the 10 Ϫ9 M range; Ref. 28) and a lack of understanding of the roles of 5-HT in the peripheral systems. One way by which physiological levels of 5-HT may have an effect on vascular tone is through the interaction with other vasoactive substances including ET-1, which could exacerbate the pathophysiological mechanisms.Evidence suggests...

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“…PPAR γ activation inhibits 5-HT 2B receptor expression by inhibiting 5-HT-induced AP-1/c-jun binding to AP-1 responsive elements in the 5-HT2BR promoter, thus suppressing the effect of 5-HT on the pulmonary vasculature. 77 Pioglitazone also attenuates vascular fibrosis and improves vascular function in spontaneously hypertensive rats 78 through increasing COX-2-derived prostaglandin I2 (PGI2) production, reducing oxidative stress, leading to increased NO bioavailability and thus to improved vasodilation in resistance arteries. 79 …”

Section: Effect Of Ppar γ Against Hypertensionmentioning

confidence: 99%

Pleiotropic Effects of Peroxisome Proliferator-Activated Receptor γ and δ in Vascular Diseases

Cheang

Fang

Tian

2013

Circ J

Self Cite

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Peroxisome proliferator-activated receptors gamma (PPAR γ ) and delta (PPARδ) are nuclear receptors that have significant physiological effects on glucose and lipid metabolism. Experimental studies in animal models of metabolic disease have demonstrated their effects on improving lipid profile, insulin sensitivity, and reducing inflammatory responses. PPAR γ and -δ are also expressed in the vasculature and their beneficial effects have been examined in various cardiovascular disease models such as atherosclerosis, hypertension, diabetic vascular complications, etc. using pharmacological ligands or genetic tools including viral vectors and transgenic mice. These studies suggest that PPAR γ and δ are antiinflammatory, antiatherogenic, antioxidant, and antifibrotic against vascular diseases. Several signaling pathways, effector molecules, as well as coactivators/repressors have been identified as responsible for the protective effects of PPAR γ and -δ in the vasculature. We discuss the pleiotropic effect of PPAR γ and δ in vascular dysfunction, including atherosclerosis, hypertension, vascular remodeling, vascular injury, and diabetic vasculopathy, in various animal models, and the major underlying mechanisms. We also compare the phenotypes of several endothelial cell/vascular smooth muscle-specific PPAR γ and -δ knockout and overexpressing transgenic mice in various disease models, and the implications underlying the functional importance of vascular PPAR γ and δ in regulating whole-body homeostasis. (Circ J 2013; 77: 2664 -2671

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Peroxisome Proliferator-Activated Receptor-γ Ameliorates Pulmonary Arterial Hypertension by Inhibiting 5-Hydroxytryptamine 2B Receptor

Cited by 45 publications

References 53 publications

Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension

Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension

Molecular interactions of serotonin (5-HT) and endothelin-1 in vascular smooth muscle cells: in vitro and ex vivo analyses

Pleiotropic Effects of Peroxisome Proliferator-Activated Receptor γ and δ in Vascular Diseases

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