lipid metabolism data.xlsx

Introduction: The heart predominantly derives its energy from fatty acid (FA) oxidation. However, the uncoupling of lipid uptake and FA oxidation can result in abnormal cardiac lipid accumulation and lipotoxicity, particularly in the context of heart failure. CD36 is a critical mediator of FA uptake in cardiac tissue. Studies have shown that genetic deletion of CD36 can prevent the onset of cardiac hypertrophy and dysfunction in murine models of obesity and diabetes. Nevertheless, the precise role of CD36 knockdown or knockout in the development and progression of cardiac dysfunction under conditions of pressure overload remains unclear. Objective: This study aims to investigate the feasibility of CD36 partially knockdown in the prevention of cardiac lipotoxicity and functional impairment in pressure overload heart. Methods: Cardiac-specific CD36 totally knockout (CKO) and partially knockdown (CKD) mice were induced by genetics deletion and AAV-9 CD36 shRNA injection, respectively. Both CD36 CKO and CKD mice were subjected to transverse aortic constriction (TAC) operation to induce cardiac pressure overload. Cardiac function was measured by echocardiography. Cardiac lipid accumulation, FA oxidation and metabolic sate were also examined. Results: TAC operation induced significant cardiac dysfunction and pathological cardiac remodeling, accompanied by aberrant intra-myocardial lipid deposition and impaired FAO capacity. CD36 CKO attenuated aberrant lipid accumulation in the failing heart, while aggravated TAC-induced cardiac energy deprivation and oxidative stress. In contrast, CD36 CKD ameliorated TAC-induced lipid accumulation and excessive oxidative stress in the mice heart, accompanied by improved mitochondrial respiration function. Moreover, CD36 CKD induced a robust increase in glycolytic flux into the TCA cycle, which led to preserved ATP generation. As a result, CD36 CKD prevented the development of pressure overload-induced cardiac hypertrophy and dysfunction. Conclusion: In this study, we reported that CD36 CKD, not CD36 CKO, was able to protect against cardiac functional impairment in the pressure-overload heart. Manipulating CD36 was a feasible strategy to achieve an optimal point which maintain cardiac energy supply while avoiding lipotoxicity.引言：心脏主要通过脂肪酸（fatty acid, FA）氧化获取能量。然而，脂质摄取与脂肪酸氧化解偶联可引发异常心脏脂质蓄积与脂毒性，在心力衰竭情境下尤为显著。CD36是心脏组织中脂肪酸摄取的关键介导因子。已有研究表明，在肥胖与糖尿病小鼠模型中，敲除CD36可预防心肌肥厚与功能障碍的发生。然而，在压力超负荷条件下，CD36敲低或敲除在心脏功能障碍的发生与进展中的精确作用仍不明确。 研究目的：本研究旨在探讨部分敲低CD36，用于预防压力超负荷心脏中的心肌脂毒性与功能损伤的可行性。 研究方法：本研究分别通过基因敲除与腺相关病毒9型（AAV-9）介导的CD36短发夹RNA（shRNA）注射，构建心脏特异性CD36全敲除（CKO）与部分敲低（CKD）小鼠模型。将CD36 CKO与CD36 CKD小鼠均行主动脉弓缩窄（transverse aortic constriction, TAC）手术以诱导心脏压力超负荷。通过超声心动图检测心脏功能，同时检测心肌脂质蓄积、脂肪酸氧化（fatty acid oxidation, FAO）与代谢状态。 研究结果：TAC手术可诱导显著的心脏功能障碍与病理性心肌重构，伴随心肌内异常脂质沉积与FAO能力受损。CD36 CKO可减轻衰竭心脏的异常脂质蓄积，但会加重TAC诱导的心肌能量匮乏与氧化应激。与之相反，CD36 CKD可改善TAC诱导的小鼠心肌脂质蓄积与过度氧化应激，同时伴随线粒体呼吸功能的改善。此外，CD36 CKD可显著提升进入三羧酸（tricarboxylic acid, TCA）循环的糖酵解通量，从而维持ATP生成。最终，CD36 CKD可阻止压力超负荷诱导的心肌肥厚与功能障碍的进展。 研究结论：本研究证实，CD36 CKD而非CD36 CKO，可对压力超负荷心脏发挥心脏功能损伤保护作用。靶向调控CD36可实现维持心脏能量供给同时避免脂毒性的最优平衡点，是一种可行的治疗策略。