Carnitine Palmitoyltransferase-1b Deficiency Aggravates Pressure Overload-Induced Cardiac Hypertrophy Caused by Lipotoxicity.
He, Lan MD, PhD; Kim, Teayoun PhD; Long, Qinqiang PhD; Liu, Jian MD, PhD; Wang, Peiyong MD, PhD; Zhou, Yiqun PhD; Ding, Yishu MD; Prasain, Jeevan PhD; Wood, Philip A. PhD; Yang, Qinglin MD, PhD
126(14):1705-1716, October 2, 2012.
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Background-: Carnitine palmitoyltransferase-1 (CPT1) is a rate-limiting step of mitochondrial [beta]-oxidation by controlling the mitochondrial uptake of long-chain acyl-CoAs. The muscle isoform, CPT1b, is the predominant isoform expressed in the heart. It has been suggested that inhibiting CPT1 activity by specific CPT1 inhibitors exerts protective effects against cardiac hypertrophy and heart failure. However, clinical and animal studies have shown mixed results, thereby creating concerns about the safety of this class of drugs. Preclinical studies using genetically modified animal models should provide a better understanding of targeting CPT1 to evaluate it as a safe and effective therapeutic approach.
Methods and Results-: Heterozygous CPT1b knockout (CPT1b /-) mice were subjected to transverse aorta constriction-induced pressure overload. These mice showed overtly normal cardiac structure/function under the basal condition. Under a severe pressure-overload condition induced by 2 weeks of transverse aorta constriction, CPT1b /- mice were susceptible to premature death with congestive heart failure. Under a milder pressure-overload condition, CPT1b /- mice exhibited exacerbated cardiac hypertrophy and remodeling compared with wild-type littermates. There were more pronounced impairments of cardiac contraction with greater eccentric cardiac hypertrophy in CPT1b /- mice than in control mice. Moreover, the CPT1b /- heart exhibited exacerbated mitochondrial abnormalities and myocardial lipid accumulation with elevated triglycerides and ceramide content, leading to greater cardiomyocyte apoptosis.
Conclusions-: CPT1b deficiency can cause lipotoxicity in the heart under pathological stress, leading to exacerbation of cardiac pathology. Therefore, caution should be exercised in the clinical use of CPT1 inhibitors.
(C) 2012 American Heart Association, Inc.