Birmingham, AL, United States
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Gong K.,Vascular Biology and Hypertension Program | Gong K.,Yangzhou University | Chen Y.-F.,Vascular Biology and Hypertension Program | Li P.,Vascular Biology and Hypertension Program | And 5 more authors.
Journal of Hypertension | Year: 2011

Objectives: Pharmacological activation of peroxisome proliferator-activated receptor gamma (PPARγ) has been shown to attenuate pressure overload-induced cardiac fibrosis, suggesting that PPARγ has an antifibrotic effect. This study tested the hypothesis that there is a functional interaction between transforming growth factor-β (TGF-β) signaling and endogenous PPARγ expression in cardiac fibroblasts and pressure overloaded heart. METHODS AND Results: We observed that, in response to pressure overload induced by transverse aortic constriction, left-ventricular PPARγ protein levels were decreased in wild-type mice, but increased in mice with an inducible overexpression of dominant negative mutation of the human TGF-β type II receptor (DnTGFβRII), in which TGF-β signaling is blocked. In isolated mouse cardiac fibroblasts, we demonstrated that TGF-β1 treatment decreased steady state PPARγ mRNA (-34%) and protein (-52%) levels, as well as PPARγ transcriptional activity (-53%). Chromatin immunoprecipitation analysis showed that TGF-β1 treatment increased binding of Smad2/3, Smad4 and histone deacetylase 1, and decreased binding of acetylated histone 3 to the PPARγ promoter in cardiac fibroblasts. Both pharmacological activation and overexpression of PPARγ significantly inhibited TGF-β1-induced extracellular matrix molecule expression in isolated cardiac fibroblasts, whereas treatment with the PPARγ agonist rosiglitazone inhibited, and treatment with the PPARγ antagonist T0070907 exacerbated chronic pressure overload-induced cardiac fibrosis and remodeling in wild-type mice in vivo. Conclusion:: These data provide strong evidence that TGF-β1 directly suppresses PPARγ expression in cardiac fibroblasts via a transcriptional mechanism and suggest that the down-regulation of endogenous PPARγ expression by TGF-β may be involved in pressure overload-induced cardiac fibrosis. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Xing D.,Vascular Biology and Hypertension Program | Kapadia A.,University of Alabama at Birmingham | Chen Y.-F.,Vascular Biology and Hypertension Program | Oparil S.,Vascular Biology and Hypertension Program | And 2 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2014

OBJECTIVE - 17β-Estradiol (E2) offers cardiovascular protection in young female animals and postmenopausal women. In contrast, randomized trials of menopausal hormones performed in older women have shown harm or no cardiovascular benefit. We hypothesize that E2 effects on vascular inflammation are age dependent. APPROACH AND RESULTS - Young (10 weeks) and aged (52 weeks) female C57BL/6 mice were used as source for primary cultures of bone marrow-derived macrophages (BMMs) and vascular smooth muscle cells (VSMCs). E2 pretreatment of cells derived from young mice attenuated C-reactive protein (CRP)-induced expression of inflammatory mediators. In contrast, E2 pretreatment of cells from aged mice did not alter (BMMs) or paradoxically exaggerated (VSMCs) inflammatory mediator response to CRP. Using E2 receptor (ER) knockout mice, we demonstrated that E2 regulates inflammatory response to CRP in BMMs via ERα and in VSMCs via ERβ. BMMs derived from aged (versus young) mice expressed significantly less ERα mRNA and protein. A selective ligand of the novel ER GPR30 reproduced the E2 effects in BMMs and VSMCs. Unlike in young mice, E2 did not reduce neointima formation in ligated carotid arteries of aged CRP transgenic mice. CONCLUSIONS - E2 attenuates inflammatory response to CRP in BMMs and VSMCs derived from young but not aged mice and reduces neointima formation in injured carotid arteries of young but not aged CRP transgenic mice. ERα expression in BMMs is greatly diminished with aging. These data suggest that vasoprotective effects of E2 are age dependent and may explain the vasotoxic effects of E2 seen in clinical trials of postmenopausal women. © 2014 American Heart Association, Inc.

Shimbo D.,Columbia University | Levitan E.B.,University of Alabama at Birmingham | Booth J.N.,University of Chicago | Calhoun D.A.,Vascular Biology and Hypertension Program | And 5 more authors.
Journal of Hypertension | Year: 2013

Objectives: Unhealthy lifestyle factors may contribute to apparent treatment resistant hypertension (aTRH). We examined associations of unhealthy lifestyle factors with aTRH in individuals taking antihypertensive medications from three or more classes. Methods: Participants (n = 2602) taking three or more antihypertensive medication classes were identified from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) study. aTRH was defined as having SBP/DBP at least 140/90 mmHg despite the use of three or more antihypertensive medication classes or the use of four or more classes to achieve blood pressure control. Lifestyle factors included obesity, physical inactivity, current smoking, heavy alcohol consumption, a low Dietary Approaches to Stop Hypertension (DASH) diet score and high sodium-to-potassium (Na/K) intake. Results: Among participants taking three or more antihypertensive medication classes, 1293 (49.7%) participants had aTRH. The prevalence of unhealthy lifestyle factors in participants with and without aTRH was 55.2 and 51.7%, respectively, for obesity, 42.2 and 40.5% for physical inactivity, 11.3 and 11.5% for current smoking, 3.1 and 4.0% for heavy alcohol consumption, 23.1 and 21.5% for low-DASH diet score, and 25.4 and 24.4% for high Na/K intake. After adjustment for age, sex, race, and geographic region of residence, none of the unhealthy lifestyle factors were associated with aTRH. The associations between each unhealthy lifestyle factor and aTRH remained nonsignificant after additional adjustment for education, income, depressive symptoms, total calorie intake, and comorbidities. Conclusions: Unhealthy lifestyle factors did not have independent associations with aTRH among individuals taking three or more antihypertensive medication classes. © 2013 Wolters Kluwer Health | Lippincott Williams Wilkins.

Hage F.G.,Vascular Biology and Hypertension Program | Oparil S.,Vascular Biology and Hypertension Program | Xing D.,Vascular Biology and Hypertension Program | Chen Y.-F.,Vascular Biology and Hypertension Program | And 3 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010

Background: We previously demonstrated that vascular injury-induced neointima formation is exaggerated in human C-reactive protein (CRP) transgenic (CRPtg) compared to nontransgenic (NTG) mice. We now test the hypothesis that complement is required for this effect. Methods and results: CRPtg and NTG with a normal complement system versus their counterparts lacking expression of complement component 3 (C3) protein (CRPtg/C3-/- and NTG/C3 -/-) underwent carotid artery ligation. Twenty-eight days later, the injured vessels in CRPtg had thicker neointimas and more immunoreactive C3 in the surrounding adventitia compared with NTG. In CRPtg/C3-/-, there was no increase in neointimal thickness compared with NTG or NTG/C3 -/-. Decreasing human CRP blood levels through administration of a selective antisense oligonucleotide eliminated the depletion of serum C3 associated with vascular injury and reduced immunoreactive C3 in the resultant lesions. In injured vessels, C3 colocalized with F4/80 (macrophage marker), and in vitro, human CRP elicited increased expression of C3 by bone marrow-derived macrophages. Conclusion: Human CRP exaggeration of neointima formation in injured mouse carotid arteries associates with decreased circulating C3 and increased tissue-localized C3. C3 elimination or pharmacological reduction of human CRP prevents CRP-driven exacerbation of the injury response. In the CRPtg model system, mouse C3 is essential for the effect of human CRP. © 2010 American Heart Association, Inc.

Pimenta E.,University of Queensland | Oparil S.,Vascular Biology and Hypertension Program
Nature Reviews Cardiology | Year: 2012

Hypertension is the most-prevalent modifiable risk factor for cardiovascular morbidity and mortality worldwide. Hypertension is highly prevalent among older adults (ĝ‰¥65 years), and aging of the population will substantially increase the prevalence of this condition. Age-related endothelial dysfunction and increased arterial stiffness contribute to the increased prevalence of hypertension, particularly systolic hypertension, among the elderly. The incidence of some forms of secondary hypertension also increases with age, mainly owing to the use of drugs (especially NSAIDs that have pressor effects) and the presence of chronic kidney disease, obstructive sleep apnea, and renal artery stenosis. Guidelines differ in thresholds and goals for antihypertensive drug therapy in the elderly because of a paucity of high-level evidence from randomized controlled trials and inconsistencies in the definition of 'elderly'. Medical treatment of hypertension reduces cardiovascular morbidity and mortality in the elderly, and all guidelines recommend lifestyle modifications and medical treatment for elderly patients whose blood pressure exceeds prescribed thresholds and who are at moderate or high cardiovascular disease risk. In the absence of comorbidities, which constitute 'compelling indications' for the use of specific antihypertensive drugs or drug classes, no clear evidence exists to support recommendations for the use of particular antihypertensive-drug classes in older adults. © 2012 Macmillan Publishers Limited. All rights reserved.

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