Abstract
BackgroundObesity, hypertension and prediabetes contribute greatly to coronary artery disease, heart failure and vascular events, and are the leading cause of mortality and morbidity in developed societies. Salt sensitivity exacerbates endothelial dysfunction. Herein, we investigated the effect of chronic glucagon like peptide-1 (GLP-1) receptor activation on the coronary microcirculation and cardiac remodeling in Zucker rats on a high-salt diet (6% NaCl).MethodsEight-week old Zucker lean (+/+) and obese (fa/fa) rats were treated with vehicle or liraglutide (LIRA) (0.1 mg/kg/day, s.c.) for 8 weeks. Systolic blood pressure (SBP) was measured using tail-cuff method in conscious rats. Myocardial function was assessed by echocardiography. Synchrotron contrast microangiography was then used to investigate coronary arterial vessel function (vessels 50–350 µm internal diameter) in vivo in anesthetized rats. Myocardial gene and protein expression levels of vasoactive factors, inflammatory, oxidative stress and remodeling markers were determined by real-time PCR and Western blotting.ResultsWe found that in comparison to the vehicle-treated fa/fa rats, rats treated with LIRA showed significant improvement in acetylcholine-mediated vasodilation in the small arteries and arterioles (< 150 µm diameter). Neither soluble guanylyl cyclase or endothelial NO synthase (eNOS) mRNA levels or total eNOS protein expression in the myocardium were significantly altered by LIRA. However, LIRA downregulated Nox-1 mRNA (p = 0.030) and reduced ET-1 protein (p = 0.044) expression. LIRA significantly attenuated the expressions of proinflammatory and profibrotic associated biomarkers (NF-κB, CD68, IL-1β, TGF-β1, osteopontin) and nitrotyrosine in comparison to fa/fa-Veh rats, but did not attenuate perivascular fibrosis appreciably.ConclusionsIn a rat model of metabolic syndrome, chronic LIRA treatment improved the capacity for NO-mediated dilation throughout the coronary macro and microcirculations and partially normalized myocardial remodeling independent of changes in body mass or blood glucose.
Highlights
Obesity, hypertension and prediabetes contribute greatly to coronary artery disease, heart failure and vascular events, and are the leading cause of mortality and morbidity in developed societies
A combination of factors including vascular inflammation, an imbalance in redox state leading to excess oxidative stress, activation of the renin–angiotensin–aldosterone and sympathetic nervous systems are involved in the cardiovascular remodeling associated with chronic exposure to high Na+ intake, obesity and diabetes, and this is often shown to be compounded by the combination of these factors
LIRA effect on renal function and glycemic profile Urinary albumin, albumin-creatinine ratio, and serum albumin values were significantly different between the fa/fa and +/+ rats
Summary
Hypertension and prediabetes contribute greatly to coronary artery disease, heart failure and vascular events, and are the leading cause of mortality and morbidity in developed societies. Hypertension and prediabetes contribute greatly to coronary artery disease, heart failure and vascular events, and the morbidity and mortality attributable to cardiovascular disease in modern societies. Obesity leads to insulin resistance, vascular oxidative stress, reduced availability of vascular nitric oxide (NO), endothelial and vasomotor dysfunction of the coronary microcirculation, which contributes greatly to the development of cardiovascular complications [1,2,3]. A combination of factors including vascular inflammation, an imbalance in redox state leading to excess oxidative stress, activation of the renin–angiotensin–aldosterone and sympathetic nervous systems are involved in the cardiovascular remodeling associated with chronic exposure to high Na+ intake, obesity and diabetes, and this is often shown to be compounded by the combination of these factors. Angiotensin type 1 receptor blockade with valsartan was only partially effective in preventing the development of vascular damage but did not reduce cardiac hypertrophy induced by the high Na+ diet
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