Aims Sterile inflammation is implicated in the development of heart failure (HF). Mitochondria plays important roles in triggering and maintaining inflammation. Mitophagy is important for regulation of mitochondrial quality and maintenance of cardiac function under pressure overload. The association of mitophagy with inflammation in HF is largely unclear. As PINK1 is a central mediator of mitophagy, our objective was to investigate its involvement in cardiac hypertrophy, and the effect of PINK1-mediated mitophagy on cGAS-STING activation during cardiac hypertrophy. Methods and results PINK1 knockout and cardiac-specific PINK1-overexpressing transgenic mice were created and subsequently subjected to transverse aortic constriction (TAC) surgery. In order to explore whether PINK1 regulates STING-mediated inflammation during HF, PINK1/STING (stimulator of interferon genes) double-knockout mice were created. Pressure overload was induced by TAC. Our findings indicate a significantly decline in PINK1 expression in TAC-induced hypertrophy. Cardiac hypertrophic stimuli caused the release of mitochondrial DNA (mtDNA) into the cytosol, activating the cGAS-STING signaling, which in turn initiated cardiac inflammation and promoted the progression of cardiac hypertrophy. PINK1 deficiency inhibited mitophagy activity, promoted mtDNA release, and then drove the overactivation of cGAS-STING signaling, exacerbating cardiac hypertrophy. Conversely, cardiac-specific PINK1 overexpression protected against hypertrophy thorough inhibition of the cGAS-STING signaling. Double-knockout mice revealed that the effects of PINK1 on hypertrophy were dependent on STING. Conclusions Our findings suggest that PINK1-mediated mitophagy plays a protective role in pressure overload-induced cardiac hypertrophy via inhibiting the mtDNA-cGAS-STING pathway.

中文翻译：

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PINK1 介导的线粒体自噬通过抑制 mtDNA 释放激活的 cGAS-STING 通路来减轻病理性心脏肥大


目的 无菌性炎症与心力衰竭 （HF） 的发生有关。线粒体在触发和维持炎症方面起着重要作用。线粒体自噬对于在压力超负荷下调节线粒体质量和维持心脏功能很重要。线粒体自噬与 HF 炎症的关联在很大程度上尚不清楚。由于 PINK1 是线粒体自噬的中枢介质，我们的目标是研究其参与心脏肥大，以及 PINK1 介导的线粒体自噬对心脏肥大期间 cGAS-STING 激活的影响。方法和结果 创造 PINK1 敲除和心脏特异性 PINK1 过表达转基因小鼠，随后进行横主动脉缩窄 （TAC） 手术。为了探讨 PINK1 是否调节 HF 期间 STING 介导的炎症，创建了 PINK1/STING （干扰素基因刺激剂） 双敲除小鼠。TAC 诱导压力超负荷。我们的研究结果表明，在 TAC 诱导的肥大中，PINK1 表达显着下降。心脏肥大刺激导致线粒体 DNA （mtDNA） 释放到胞质溶胶中，激活 cGAS-STING 信号传导，进而引发心脏炎症并促进心脏肥大的进展。PINK1 缺陷抑制线粒体自噬活性，促进 mtDNA 释放，进而驱动 cGAS-STING 信号转导的过度激活，加剧心脏肥大。相反，心脏特异性 PINK1 过表达通过抑制 cGAS-STING 信号传导防止肥大。双基因敲除小鼠显示 PINK1 对肥大的影响取决于 STING。 结论 我们的研究结果表明，PINK1 介导的线粒体自噬通过抑制 mtDNA-cGAS-STING 通路在压力超负荷诱导的心脏肥大中发挥保护作用。