Adipocyte fatty acid binding protein (A-FABP) is a potential mediator of heart dysfunction and failure related to obesity

Abstract

Obesity predisposes to the development of diabetes, hypertension and dyslipidemia, which are the risk factors for the development of cardiac artery disease and ischemic cardiomyopathy. It is also an independent risk factor for the development of heart failure. Adipocyte fatty acid binding protein (A-FABP) is an adipokine that mainly expressed in adipocytes and macrophages and can be released into the circulation. Emerging clinical evidence suggest that A-FABP is a key link between obesity and cardiac dysfunction as elevated circulating A-FABP levels are positively associated with cardiac contractile dysfunction of obese subjects as well as left ventricular mass and myocardial performance index in patients with obstructive sleep apnea syndrome. Circulating A-FABP is also significantly increased in Chinese subjects with heart failure and is independently associated with the deterioration of heart function. Here we investigate the pathological role of A-FABP in cardiomyopathy associated with obesity using A-FABP knockout (KO) mice and their wildtype (WT) littermates. A-FABP KO mice and their WT littermates were fed with standard chow (STC) or high fat high cholesterol diet (HFHC) for 24 weeks with or without treatment of selective A-FABP inhibitor BMS309403 (BMS). The circulating level and cardiac expression of A-FABP were markedly elevated in WT mice after prolonged HFHC diet feeding. A-FABP deficiency protected against HFHC diet induced- hypertension and -impairment of systolic and diastolic function in mice. Compared to WT mice, diet-induced cardiomyocyte hypertrophy, cardiac lipid accumulation and fibrosis were ameliorated in A-FABP KO mice. These protective actions of A-FABP deficiency were accompanied by reduced cardiac inflammation and endoplasmic reticulum (ER) stress. Consistently, HFHC diet-induced cardiomyocyte hypertrophy and cardiac collagen deposition were significantly diminished in WT mice treated with BMS. In conclusion, A-FABP deficiency protects mice against cardiomyopathy and heart dysfunction associated with obesity. A-FABP may be the therapeutic target for the treatment of obesity-related cardiomyopathy.