Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (Y.T., Y.S., T.M., Y.X., D.X.).
Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, China (M.F., H.Z., S.S., Y.Z., K.W.).
Circulation. 2023 May 30;147(22):1684-1704. doi: 10.1161/CIRCULATIONAHA.123.064121. Epub 2023 Apr 17.
A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear.
We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy.
We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by deficiency, and heart failure induced by pressure overload, as well.
Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.
很大一部分特发性和家族性扩张型心肌病（DCM）病例没有明显的因果遗传变异。尽管代谢应激反应的改变已被牵涉其中，但 DCM 发病机制的分子机制仍不清楚。JMJD 家族蛋白最初被鉴定为组蛋白去乙酰化酶，已被证明与许多心血管疾病有关。尽管它们的功能越来越多样化，但 JMJD 家族成员是否在 DCM 中发挥作用仍不清楚。
我们检查了 DCM 患者的 Jmjd4 表达，并在体内条件性删除和过表达 Jmjd4 ，以研究其在 DCM 中的作用。使用 RNA 测序、代谢物谱分析和质谱分析来剖析 Jmjd4 调节心脏代谢和肥大的分子机制。
我们发现 Jmjd4 的表达在 DCM 患者的心脏中显著降低。诱导心肌细胞特异性删除 Jmjd4 导致自发性 DCM，线粒体呼吸严重受损。与 Pkm1 相比，Pkm2 的活性较低，Pkm1 通常不存在于健康的成年心肌细胞中，但在心肌病中升高，我们发现 Pkm2 在删除 Jmjd4 的心脏中大量积累。机制上发现 Jmjd4 与 Hsp70 相互作用，通过伴侣介导的自噬介导 Pkm2 的降解，这依赖于 Jmjd4 对 Pkm2 的 K66 位的羟化。通过增强丰富但活性较低的 Pkm2 的酶活性，Pkm2 激动剂 TEPP-46 对 Jmjd4 缺乏引起的 DCM 和压力超负荷引起的心力衰竭有显著的治疗作用。
我们的研究结果确定了 Jmjd4 通过降解 Pkm2 维持成年心肌细胞代谢平衡的新作用，并表明 Jmjd4 和 Pkm2 可能成为治疗 DCM 以及其他代谢功能障碍性心脏疾病的治疗靶点。
