Interference with PPARγ Function in Smooth Muscle Causes Vascular Dysfunction and Hypertension

Halabi, Carmen M.; Beyer, Andreas; Lange, Willem J. de; Keen, Henry L.; Baumbach, Gary L.; Faraci, Frank M.; Sigmund, Curt D.

doi:10.1016/j.cmet.2007.12.008

Cited by 159 publications

(213 citation statements)

References 49 publications

(51 reference statements)

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“…Thus, humans with the dominant-negative P467L mutation are hypertensive, and we have previously shown that an equivalent PPAR␥-P465L mutation in mice causes a Ϸ7 mm Hg increase in blood pressure (11). Transgenic mice that overexpress the human PPAR␥ gene with a P467L mutation in vascular smooth muscle cells also have elevated blood pressure (22). Our demonstration of an inverse relationship between genetically determined levels of PPAR␥ expression and blood pressure is consistent with these observations.…”

Section: Discussionsupporting

confidence: 80%

Genetic variations in peroxisome proliferator-activated receptor γ expression affect blood pressure

Tsai

Xu²,

Smithies

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Metabolic syndrome, a clustering of conditions including obesity, insulin resistance, and hypertension, is a risk factor for cardiovascular morbidity and mortality. Because peroxisome proliferatoractivated receptor ␥ (PPAR␥) regulates adipocyte differentiation and lipid metabolism and is the molecular target of a class of insulin sensitizers, genetic variants that alter Pparg gene expression are potential contributors to the metabolic syndrome. To test this possibility, we generated mice having 182% of the normal steadystate level of PPAR␥ mRNA by replacing the 3 -UTR of the natural Pparg gene with that of the ␤-globin gene, thereby stabilizing the Pparg transcripts. This increase in PPAR␥ mRNA level had no apparent consequences in various physiological parameters, except that the mice repeatedly showed a trend toward lower blood pressures (by about 3 mm Hg) than their WT littermates. In contrast, the opposite trend, toward increased blood pressure, was observed in mice with genetically reduced levels of PPAR␥ mRNA as a consequence of insertion of an allele with an mRNAdestabilizing sequence into the endogenous 3 -UTR of the Pparg gene. By combining 12 sets of blood pressure measurements in more than 350 mutant mice having PPAR␥ expression levels varying from 28% to 182% and more than 280 WT littermates, we show that a 2-fold genetic increase (or decrease) in PPAR␥ expression levels decreases (or increases) blood pressure by about 2.8 mm Hg. Thus, our experiments demonstrate that quantitative variants causing decreased Pparg expression are a potential causative risk factor for essential hypertension.3Ј-UTR ͉ hypertension ͉ metabolic syndrome ͉ mouse models

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Section: Discussionsupporting

confidence: 80%

Genetic variations in peroxisome proliferator-activated receptor γ expression affect blood pressure

Tsai

Xu²,

Smithies

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, the human PPARg dominant negative mutant induces hypertension and metabolic dysfunctions (Barroso et al 1999), and vascular smooth muscle cell (VSMC)-specific PPARg dominant negative mutant transgenic mice develop impaired vasodilation and hypertension (Sugawara et al 2001). We have previously shown that PPARg agonists suppress angiotensin II (AII) type 1 receptor (Halabi et al 2008) and thromboxane receptor (Sugawara et al 2002) in VSMCs as well as macrophage activation (Jiang et al 1998, Ricote et al 1998 and thromboxane synthase expression in macrophages (Ikeda et al 2000). Thus, VSMCs and macrophages are important targets of PPARg against atherosclerosis/hypertension.…”

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor- suppresses CYP11B2 expression and aldosterone production

Uruno¹,

Matsuda²,

Noguchi³

et al. 2010

Journal of Molecular Endocrinology

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Peroxisome proliferator-activated receptor-g (PPARg) is a nuclear receptor for the antidiabetic agent thiazolidinedione, which exerts various physiological activities, independent of lowering blood glucose. However, the role of PPARg in aldosterone production has not been clarified. The objective of this study was to investigate the effect of PPARg on aldosterone synthase gene (CYP11B2) expression and aldosterone production. Localization of PPARg expression in normal adrenal cortex was determined by immunohistochemistry. Aldosterone production and CYP11B2 expression levels were determined using human adrenocortical carcinoma H295R cells. Pioglitazone suppressed angiotensin II-induced aldosterone secretion and CYP11B2 expression. PPARg was expressed in zona glomerulosa in human normal adrenal gland. PPARg overexpression enhanced pioglitazone-mediated CYP11B2 transrepression. The pioglitazone-mediated suppression of aldosterone secretion and CYP11B2 expression were canceled by PPARg L466A/E469A mutant. Pioglitazone also suppressed potassium-mediated CYP11B2 induction, but not N6-

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“…PPAR-g is expressed in both vascular endothelial and smooth muscle cells, and shown to be critically involved in the development of vascular complications and inflammation and hypertension. (146)(147)(148)(149) In fact, the anti-proliferative, anti-atherosclerosis properties of PPAR-g have been shown to suppress VSMC proliferation, which could be at least in part mediated by its effects on suppression of telomerase activity (proproliferation). This is supported by the findings that PPAR-g activation suppresses telomerase in cultured VSMC (117).…”

Section: Telomerase As a Therapeutic Target In Cardiovascular Diseasementioning

confidence: 99%

Telomeres and Telomerase in The Aging Heart

2017

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B ACKGROUND:Aging per se is a risk factor for reduced cardiac function and heart diseases, even when adjusted for aging-associated cardiovascular risk factors. Accordingly, aging-related biochemical and cell-biological changes lead to pathophysiological conditions, especially reduced heart function and heart disease. CONTENT:Telomere dysfunction induces a profound p53-dependent repression of the master regulators of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor gamma coactivator (PGC)-1a and PGC-1b in the heart, which leads to bioenergetic compromise due to impaired oxidative phosphorylation and ATP generation. This telomere-p53-PGC mitochondrial/ metabolic axis integrates many factors linked to heart aging including increased DNA damage, p53 activation, mitochondrial, and metabolic dysfunction and provides a molecular basis of how dysfunctional telomeres can compromise cardiomyocytes and stem cell compartments in the heart to precipitate cardiac aging. SUMMARY:The aging myocardium with telomere shortening and accumulation of senescent cells restricts the tissue regenerative ability, which contributes to systolic or diastolic heart failure. Moreover, patients with ion-channel defects might have genetic imbalance caused by oxidative stress-related accelerated telomere shortening, which may subsequently cause sudden cardiac death. Telomere length can serve as a marker for the biological status of previous cell divisions and DNA damage with inflammation and oxidative stress. It can be integrated into current risk prediction and stratification models for cardiovascular diseases and can be used in precise personalized treatments. KEYWORDS: aging, telomere, telomerase, aging heart, mitochondria, cardiac stem cell Indones Biomed J. 2017; 9(3): 129-42 Abstract Introduction

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Interference with PPARγ Function in Smooth Muscle Causes Vascular Dysfunction and Hypertension

Cited by 159 publications

References 49 publications

Genetic variations in peroxisome proliferator-activated receptor γ expression affect blood pressure

Genetic variations in peroxisome proliferator-activated receptor γ expression affect blood pressure

Peroxisome proliferator-activated receptor- suppresses CYP11B2 expression and aldosterone production

Telomeres and Telomerase in The Aging Heart

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