心肌内源性HMGB1通过调控calpain相关程序性死亡保护扩张型心肌病的分子机制

钙蛋白酶（calpain）在扩张型心肌病（DCM）显著上调表达并促进心肌细胞死亡，但调控机制不明。我们前期研究发现心肌特异性calpain-4或者HMGB1单敲小鼠心脏正常，但双敲后可自发产生DCM，提示心肌内源性HMGB1具有显著保护作用。进一步研究发现该保护主要通过调控calpain相关心肌细胞程序性坏死和焦亡实现，而非凋亡。本研究我们提出：心肌内源性HMGB1通过结合并抑制PARP1活性，调控calpain和下游RIPK1/3-MLKL介导的程序性坏死以及caspase 1-GSDME介导的焦亡。此外，calpain相关程序性坏死也可通过RIPK-PARP1通路，进一步减少具有保护作用的心肌内源性HMGB1，加剧心肌死亡，最终推动DCM不可逆性进展为心衰。本研究旨在分析心肌内源性HMGB1调控calpain相关程序性死亡的机制，为DCM的新型防治策略研制提供可能靶点。

Up-regulated calpains significantly promote cardiomyocyte death in dilated cardiomyopathy (DCM), but the regulatory mechanism is unknown. Our preliminary data showed that myocardium-specific calpain-4 or HMGB1 knock-down mice had normal heart, but spontaneously occured DCM when these two genes were simultaneously knocked down, suggesting that myocardial endogenous HMGB1 had significant protective effects. Further study showed that this protection was mainly through regulating calpain-related myocardial necroptosis and pyroptosis, but not apoptosis. In this study, we proposed that myocardial endogenous HMGB1 protected calpain-related necroptosis and pyroptosis by inhibiting PARP1-calpain and downstream RIPK1/3-MLKL and caspase 1-GSDME signaling pathways. In addition, calpain-related necrosis can also in turn reduce the protective effect of myocardial endogenous HMGB1 through modulating PARP1 by RIPK1, and promote the irreversible progression of DCM to heart failure. The aim of this study was to analyze the mechanism by which myocardial endogenous HMGB1 regulated calpain-related programmed cell death, and provided a possible target for the development of new prevention and treatment strategies for DCM.