Carnitine palmitoyltransferase-1b deficiency aggravates pressure overload-induced cardiac hypertrophy caused by lipotoxicity.
Carnitine palmitoyltransferase-1b deficiency aggravates pressure overload-induced cardiac hypertrophy caused by lipotoxicity.
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DOI：
10.1161/circulationaha.111.075978
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发表时间：
2012-10-02
期刊：
影响因子：
37.8
通讯作者：
Yang Q
中科院分区：
文献类型：
--
作者：
He L;Kim T;Long Q;Liu J;Wang P;Zhou Y;Ding Y;Prasain J;Wood PA;Yang Q
肉毒碱棕榈酰转移酶1（CPT 1）是线粒体β-氧化的限速步骤，通过控制线粒体摄取长链酰基辅酶A。肌肉亚型CPT 1b是心脏中表达的主要亚型。已经表明，通过特异性CPT-1抑制剂抑制CPT-1活性对心脏肥大和心力衰竭发挥保护作用。然而，临床和动物研究显示了混合的结果，从而对这类药物的安全性表示担忧。使用转基因动物模型的临床前研究应该提供对靶向CPT 1的更好理解，以评估其作为安全有效的治疗方法。对杂合子CPT 1b敲除小鼠（CPT 1b +/−）进行横主动脉缩窄（TAC）诱导的压力超负荷。这些小鼠在基础条件下显示明显正常的心脏结构/功能。在由两周的横向主动脉缩窄（TAC）诱导的严重压力超负荷条件下，CPT 1b +/−小鼠容易因充血性心力衰竭而过早死亡。在较温和的压力超负荷条件下，与野生型同窝小鼠相比，CPT 1b +/−小鼠表现出加剧的心脏肥大和重塑。CPT 1b +/−小鼠的心脏收缩受损更明显，离心性心脏肥大更大。此外，CPT 1b +/−心脏表现出线粒体异常和心肌脂质蓄积加剧，甘油三酯和神经酰胺含量升高，导致心肌细胞凋亡增加。我们的结论是，CPT 1b缺乏可导致病理应激下的心脏脂毒性，导致心脏病理恶化。因此，CPT-1抑制剂的临床使用应谨慎。
Carnitine palmitoyltransferase 1(CPT1) is a rate-limiting step of mitochondrial β-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 CPT-1 activity by specific CPT-1 inhibitors exerts protective effects against cardiac hypertrophy and heart failure. However, clinical and animal studies have shown mixed results, thereby posting concerns on the safety of this class of drugs. Preclinical studies using genetically modified animal models should provide a better understanding of targeting CPT1 in order to evaluate it as a safe and effective therapeutic approach. Heterozygous CPT1b knockout mice (CPT1b+/−) were subjected to transverse aorta constriction (TAC)-induced pressure-overload. These mice showed overtly normal cardiac structure/function under the basal condition. Under a severe pressure-overload condition induced by two weeks of transverse aorta constriction (TAC), 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 that in wild-type littermates. There were more pronounced impairments of cardiac contraction with greater eccentric cardiac hypertrophy in CPT1b+/− than in controlled mice. Moreover, the CPT1b+/− heart exhibited exacerbated mitochondrial abnormalities and myocardial lipid accumulation with elevated triglycerides and ceramide content, leading to greater cardiomyocytes apoptosis. We conclude that CPT1b deficiency can cause lipotoxicity in the heart under pathological stress, leading to exacerbation of cardiac pathology. Therefore, caution should be applied in the clinical use of CPT-1 inhibitors.