Short-chain acyl-CoA dehydrogenase: a novel and promising therapeutic target for heart failure via modulation of mitochondrial fatty acid oxidation.

OBJECTIVE

Heart failure is a major global health problem with high morbidity and mortality. Dysregulated fatty acid oxidation (FAO) appears to be an important therapeutic target for directly improving cardiac function. Short-chain acyl-CoA dehydrogenase (SCAD) is a key enzyme in FAO. This study aimed to elucidate the role of SCAD in heart failure.

METHODS

Left anterior descending (LAD) coronary artery ligation in rats was used as an acute heart failure model, whereas aged spontaneously hypertensive rats (SHRs, 20 months old) served as a chronic heart failure model. We generated conventional SCAD knockout (KO) mice to evaluate the role of SCAD in heart failure. Additionally, adenovirus-mediated SCAD overexpression was employed. Heart sections from patients with heart failure were analyzed for SCAD expression.

RESULTS

SCAD expression was downregulated in chronic heart failure in aged SHRs. Subsequent experiments showed that aged SCAD-deficient mice (2 years old) developed spontaneous heart failure. Moreover, SCAD KO markedly exacerbated heart failure in transverse aortic constriction-operated mice. Conversely, adenovirus-mediated SCAD overexpression suppressed tert-butyl hydroperoxide-induced cardiomyocyte apoptosis in vitro and protected the heart against LAD ligation-induced heart failure after myocardial infarction in rats. Similarly, SCAD expression was decreased in the hearts of patients with heart failure.

CONCLUSION

SCAD has a negative regulatory effect on heart failure and may represent a novel therapeutic target.