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Nicholls S.J.,Cleveland Clinic | Jahangiri A.,Graduate Center for Nutritional science | Jahangiri A.,Cardiovascular Research Center | Jahangiri A.,University of Kentucky
Current Cardiovascular Risk Reports | Year: 2011

Low high-density lipoprotein cholesterol (HDL-C) is the most prevalent lipid abnormality in patients with known coronary heart disease (CHD). Since the 1960 s, epidemiologic studies have shown an inverse relationship between HDL-C levels and risk of developing CHD. This data correlates a 1-mg/dL increase in HDL-C with a 2% to 3% reduction in CHD events. The prevalence of low HDL-C among patients with CHD has prompted multiple trials to increase the concentration or mimic the function of HDL in an attempt to reduce cardiovascular events. This review outlines the cardioprotective functions of HDL-C, describes conditions that modify HDL structure and function, and presents an overview of clinical trials on HDL-raising therapies. © 2010 Springer Science+Business Media, LLC. Source

Daugherty A.,Saha Cardiovascular Research Center | Daugherty A.,Graduate Center for Nutritional science | Rateri D.L.,Saha Cardiovascular Research Center | Howatt D.A.,Saha Cardiovascular Research Center | And 2 more authors.
PLoS ONE | Year: 2013

Background:AT2 receptors have an unclear function on development of abdominal aortic aneurysms (AAAs), although a pharmacological approach using the AT2 receptor antagonist PD123319 has implicated a role. The purpose of the present study was to determine the role of AT2 receptors in AngII-induced AAAs using a combination of genetic and pharmacological approaches. We also defined effects of AT2 receptors in AngII-induced atherosclerosis and thoracic aortic aneurysms.Methods and Results:Male AT2 receptor wild type (AT2 +/y) and deficient (AT2 -/y) mice in an LDL receptor -/- background were fed a saturated-fat enriched diet, and infused with either saline or AngII (500 ng/kg/min). AT2 receptor deficiency had no significant effect on systolic blood pressure during AngII-infusion. While AngII infusion induced AAAs, AT2 receptor deficiency did not significantly affect either maximal width of the suprarenal aorta or incidence of AAAs. The AT2 receptor antagonist PD123319 (3 mg/kg/day) and AngII were co-infused into male LDL receptor -/- mice that were either AT2 +/y or -/y. PD123319 had no significant effect on systolic blood pressure in either wild type or AT2 receptor deficient mice. Consistent with our previous findings, PD123319 increased AngII-induced AAAs. However, this effect of PD123319 occurred irrespective of AT2 receptor genotype. Neither AT2 receptor deficiency nor PD123319 had any significant effect on AngII-induced thoracic aortic aneurysms or atherosclerosis.Conclusions:AT2 receptor deficiency does not affect AngII-induced AAAs, thoracic aortic aneurysms and atherosclerosis. PD123319 augments AngII-induced AAAs through an AT2 receptor-independent mechanism. © 2013 Daugherty et al. Source

Zheng Y.,Graduate Center for Nutritional science | Morris A.,The Gill Heart Institute | Sunkara M.,The Gill Heart Institute | Layne J.,Graduate Center for Nutritional science | And 2 more authors.
Journal of Nutritional Biochemistry | Year: 2012

Flavonoids, such as the tea catechin epigallocatechin-gallate (EGCG), can protect against atherosclerosis by decreasing vascular endothelial cell inflammation. Heme oxygenase-1 (HO-1) is an enzyme that plays an important role in vascular physiology, and its induction may provide protection against atherosclerosis. Heme oxygenase-1 can be compartmentalized in caveolae in endothelial cells. Caveolae are plasma microdomains important in vesicular transport and the regulation of signaling pathways associated with the pathology of vascular diseases. We hypothesize that caveolae play a role in the uptake and transport of EGCG and mechanisms associated with the anti-inflammatory properties of this flavonoid. To test this hypothesis, we explored the effect of EGCG on the induction of NF-E2-related factor (Nrf2) and HO-1 in endothelial cells with or without functional caveolae. Treatment with EGCG activated Nrf2 and increased HO-1 expression and cellular production of bilirubin. In addition, EGCG rapidly accumulated in caveolae, which was associated with caveolin-1 displacement from the plasma membrane towards the cytosol. Similar to EGCG treatment, silencing of caveolin-1 by siRNA technique also resulted in up-regulation of Nrf2, HO-1 and bilirubin production. These data suggest that EGCG-induced caveolin-1 displacement may reduce endothelial inflammation. © 2012 Elsevier Inc. Source

Wang Y.,University of Kentucky | Su K.,University of Kentucky | Sabeva N.S.,Central University of the Caribbean | Ji A.,University of Kentucky | And 6 more authors.
Metabolism: Clinical and Experimental | Year: 2015

Objective Mice lacking leptin (ob/ob) or its receptor (db/db) are obese, insulin resistant, and have reduced levels of biliary cholesterol due, in part, to reduced levels of hepatic G5G8. Chronic leptin replacement restores G5G8 abundance and increases biliary cholesterol concentrations, but the molecular mechanisms responsible for G5G8 regulation remain unclear. In the current study, we used a series of mouse models to address potential mechanisms for leptin-mediated regulation of G5G8. Methods and Results We acutely replaced leptin in ob/ob mice and deleted hepatic leptin receptors in lean mice. Neither manipulation altered G5G8 abundance or biliary cholesterol. Similarly, hepatic vagotomy had no effect on G5G8. Alternatively, G5G8 may be decreased in ob/ob and db/db mice due to ER dysfunction, the site of G5G8 complex assembly. Overexpression of the ER chaperone GRP78 using an adenoviral vector restores ER function and reduces steatosis in ob/ob mice. Therefore, we determined if AdGRP78 could rescue G5G8 in db/db mice. As in ob/ob mice, AdGRP78 reduced expression of lipogenic genes and plasma triglycerides in the db/db strain. Both G5 and G8 protein levels increased as did total biliary cholesterol, but in the absence of changes in G5 or G8 mRNAs. The increase in G5G8 was associated with increases in a number of proteins, including the ER lectin chaperone, calnexin, a key regulator of G5G8 complex assembly. Conclusions Leptin signaling does not directly regulate G5G8 abundance. The loss of G5G8 in mice harboring defects in the leptin axis is likely associated with compromised ER function. © 2015 Elsevier Inc. Source

Chen X.,University of Kentucky | Chen X.,Laboratory of Cardiovascular Disease | Lu H.,University of Kentucky | Zhao M.,University of Kentucky | And 6 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2013

Objective-This study determined the role of angiotensin-converting enzyme (ACE) on the development of angiotensin I-induced atherosclerosis and the contribution of leukocyte-specific expression of this enzyme. Approach and Results-To define the contribution of ACE-dependent activity to angiotensin II synthesis in atherosclerotic development, male low-density lipoprotein receptor mice were fed a fat-enriched diet and infused with either angiotensin I or angiotensin II. The same infusion rate of these peptides had equivalent effects on atherosclerotic development. Coinfusion of an ACE inhibitor, enalapril, ablated angiotensin I-augmented atherosclerosis but had no effect on angiotensin II-induced lesion development. ACE protein was detected in several cell types in atherosclerotic lesions, with a predominance in macrophages. This cell type secreted angiotensin II, which was ablated by ACE inhibition. To study whether leukocyte ACE contributed to atherosclerosis, irradiated male low-density lipoprotein receptor mice were repopulated with bone marrow-derived cells from either ACE or ACE mice and fed the fat-enriched diet for 12 weeks. Chimeric mice with ACE deficiency in bone marrow-derived cells had modestly reduced atherosclerotic lesions in aortic arches but had no effects in aortic roots. Conclusions-ACE mediates angiotensin I-induced atherosclerosis, and ACE expression in leukocytes modestly contributes to atherosclerotic development in hypercholesterolemic mice. © 2013 American Heart Association, Inc. Source

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