Abstract
BackgroundFatty acid (FA) catabolism abnormality has been proved to play an important role in obesity-related cardiomyopathy. We hypothesized that cardiospecific suppression of CD36, the predominant membrane FA transporter, would protect against obesity-related cardiomyopathy.MethodsFour-wk-old male C57BL/6 J mice were fed with either high-fat-diet (HFD) or control-normal-diet for 2 wk. Then they were subjected to intramyocardial injection with recombinant lentiviral vectors containing short hairpin RNAs to selectively downregulate the expression of either cardiac CD36 or irrelevant gene by RNA interference. After a 10-wk continuation of the diet, biochemical, functional, morphological, histological, metabolic and molecular profiles were assessed.ResultsHFD administration elicited obesity, cardiac hypertrophy and systolic dysfunction accompanied with elevated serum levels of blood urea nitrogen (BUN), creatinine, fasting serum glucose (FSG), total cholesterol (TC) and triglyceride. Additionally, HFD consumption promoted lipid accumulation and reactive oxygen species (ROS) generation in the cardiomyocytes. Cardiospecific CD36 inhibition protected against HFD induced cardiac remodeling by decreasing heart/body weight ratio, increasing left ventricular (LV) ejection fraction and fractional shortening as well as normalizing LV diameter, without influencing body weight gain. Inhibition of cardiac CD36 also mitigated obesity induced alteration in BUN, creatinine and triglyceride, but had no effect on FSG or TC. Moreover, cardiospecific CD36 deficiency corrected myocardial lipid overaccumulation and intracellular ROS overproduction that were induced by HFD feeding.ConclusionsCardiospecific CD36 inhibition protects against the aggravation of cardiac functional and morphological changes associated with HFD induced obesity. CD36 represents a potential therapeutic target for obesity cardiomyopathy.
Highlights
Fatty acid (FA) catabolism abnormality has been proved to play an important role in obesity-related cardiomyopathy
We found mice receiving HFD had higher levels of blood urea nitrogen (BUN), creatinine, fasting serum glucose (FSG), triglyceride and total cholesterol (TC) than mice receiving CND, whereas the levels of Alanine aminotransferase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) remained comparable among all experimental groups
HFD feeding induced obesity and altered biochemical parameters After a 12-wk HFD feeding, mice exhibited obvious obesity that was characterized by significant increase in body weight (33.05 ± 0.93 g for obese mice compared to 26.95 ± 0.96 g for normal mice, P < 0.001)
Summary
Fatty acid (FA) catabolism abnormality has been proved to play an important role in obesity-related cardiomyopathy. With the spread of sedentary lifestyle, obesity becomes a major global health issue It is regarded as an energy balance disorder in which inappropriate expansion and dysfunction of adipose tissue leading to a pandemic of type 2 diabetes [1] and increased risk of developing cardiovascular diseases [2, 3]. Accumulated experimental evidence supports an association between obesity and morphological and functional changes in hearts of both humans [3,4,5,6] and animals [7,8,9] Many of these changes, such as cardiac hypertrophy, compromised left ventricular (LV) function, are believed to be precursors of more overt forms of cardiac dysfunction and heart failure. For the past few years, certain metabolic disorders, observed mainly in animal models, have attracted increasing attention [9,10,11,12,13,14]
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