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Abstract：
Cardiac remodeling is the primary pathological feature of chronic heart failure (HF). Exploring the characteristics of cardiac remodeling in the very early stages of HF and identifying targets for intervention are essential for discovering novel mechanisms and therapeutic strategies. Silent mating type information regulation 2 homolog 3 (SIRT3), as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolism. However, whether SIRT3 plays a role in cardiac remodeling by regulating the biosynthesis of mitochondrial cardiolipin (CL) is unknown. In this study, we induced pressure overload in wild-type (WT) and SIRT3 knockout (SIRT3-/-) mice via transverse aortic constriction (TAC). Compared with WT mouse hearts, the hearts of SIRT3-/- mice exhibited more-pronounced cardiac remodeling and fibrosis, greater reactive oxygen species (ROS) production, decreased mitochondrial-membrane potential (ΔΨm), and abnormal mitochondrial morphology after TAC. Furthermore, SIRT3 deletion aggravated TAC-induced decrease in total CL content, which might be associated with the downregulation of the CL synthesis related enzymes cardiolipin synthase 1 (CRLS1) and phospholipid-lysophospholipid transacylase (TAFAZZIN). In our in vitro experiments, SIRT3 overexpression prevented angiotensin II (AngII)- induced aberrant mitochondrial function, CL biosynthesis disorder, and peroxisome proliferator-activated receptor gamma (PPARγ) downregulation in cardiomyocytes; meanwhile, SIRT3 knockdown exacerbated these effects. Moreover, the addition of GW9662, a PPARγ antagonist, partially counteracted the beneficial effects of SIRT3 overexpression. In conclusion, SIRT3 regulated PPARγ-mediated CL biosynthesis, maintained the structure and function of mitochondria, and thereby protected the myocardium against cardiac remodeling.
摘要：
心脏重塑是慢性心力衰竭(HF)的主要病理特征。探索HF早期阶段的心脏重塑特征并确定干预目标对于发现新机制和治疗策略至关重要。无声交配类型信息调节2同源物3(SIRT3)，作为主要的线粒体烟酰胺腺嘌呤二核苷酸（NAD）依赖性脱乙酰酶，是线粒体代谢所必需的。然而,SIRT3是否通过调节线粒体心磷脂(CL)的生物合成在心脏重塑中发挥作用尚不清楚.在这项研究中,我们通过横向主动脉缩窄（TAC）在野生型（WT）和SIRT3敲除（SIRT3-/-）小鼠中诱导了压力超负荷。与WT小鼠心脏相比，SIRT3-/-小鼠的心脏表现出更明显的心脏重塑和纤维化，更多的活性氧(ROS)产生，线粒体膜电位降低(ΔkW)，TAC后线粒体形态异常。此外，SIRT3缺失加重了TAC诱导的总CL含量降低，这可能与CL合成相关酶心磷脂合成酶1（CRLS1）和磷脂溶血磷脂转酰酶（TAFAZZIN）的下调有关。在我们的体外实验中，SIRT3过表达阻止血管紧张素II（AngII）-诱导的异常线粒体功能，CL生物合成障碍，和过氧化物酶体增殖物激活受体γ(PPARγ)在心肌细胞中的下调;同时,SIRT3敲除加剧了这些影响。此外，添加PPARγ拮抗剂GW9662，部分抵消了SIRT3过表达的有益作用。总之,SIRT3调节PPARγ介导的CL生物合成，维持线粒体的结构和功能，从而保护心肌免受心脏重塑。
