Abstract：
HHATL, previously implicated in cardiac hypertrophy in the zebrafish model, has emerged as a prioritized HCM risk gene. We identified six rare mutations in HHATL, present in 6.94 % of nonsarcomeric HCM patients (5/72). Moreover, a decrease of HHATL in the heart tissue from HCM patients and cardiac hypertrophy mouse model using transverse aortic constriction was observed. Despite this, the precise pathogenic mechanisms underlying HHATL-associated cardiac hypertrophy remain elusive. In this study, we observed that HHATL downregulation in H9C2 cells resulted in elevated expression of hypertrophic markers and reactive oxygen species (ROS), culminating in cardiac hypertrophy and mitochondrial dysfunction. Notably, the bioactive form of SHH, SHHN, exhibited a significant increase, while the mitochondrial fission protein dynamin-like GTPase (DRP1) decreased upon HHATL depletion. Intervention with the SHH inhibitor RU-SKI 43 or DRP1 overexpression effectively prevented Hhatl-depletion-induced cardiac hypertrophy, mitigating disruptions in mitochondrial morphology and membrane potential through the SHH/DRP1 axis. In summary, our findings suggest that HHATL depletion activates SHH signaling, reducing DRP1 levels and thereby promoting the expression of hypertrophic markers, ROS generation, and mitochondrial dysfunction, ultimately leading to cardiac hypertrophy. This study provides additional compelling evidence supporting the association of HHATL with cardiac hypertrophy.
摘要：
HHATL,先前在斑马鱼模型中与心脏肥大有关，已成为优先考虑的HCM风险基因。我们在HHATL中发现了六个罕见的突变，存在于6.94%的非肌节型HCM患者中(5/72)。此外，观察到HCM患者和使用横主动脉缩窄的心肌肥厚小鼠模型的心脏组织中HHATL的减少。尽管如此,HHATL相关心脏肥大的确切致病机制仍然难以捉摸.在这项研究中,我们观察到H9C2细胞中HHATL下调导致肥大性标志物和活性氧（ROS）的表达升高，最终导致心脏肥大和线粒体功能障碍。值得注意的是,SHH的生物活性形式，SHHN,显着增加，而线粒体裂变蛋白动力蛋白样GTP酶（DRP1）在HHATL耗尽后降低。SHH抑制剂RU-SKI43或DRP1过表达的干预可有效预防Hhatl耗竭诱导的心脏肥大，通过SHH/DRP1轴减轻线粒体形态和膜电位的破坏。总之,我们的发现表明HHATL耗竭激活SHH信号，降低DRP1水平，从而促进肥大性标志物的表达，ROS生成，和线粒体功能障碍，最终导致心脏肥大.这项研究提供了其他令人信服的证据支持HHATL与心脏肥大的关联。
