Hyperglycemia is an independent risk factor for diabetic heart failure. However, the mechanisms that mediate hyperglycemia-induced cardiac damage remain poorly understood. Previous studies have shown an association between lysosomal dysfunction and diabetic heart failure. Lysosomal membrane permeabilization (LMP) is a prominent feature of lysosomal dysfunction. We examined if high glucose (HG) induces LMP in cardiomyocyte. Immunofluorescent microscopy showed the release of cathepsin D (CTSD) from lysosome under HG, suggesting that HG induces LMP. To determine whether LMP and the ensuing CTSD expression play a role in HG-induced cardiomyocyte injury, we treated cells with siRNA targeting CTSD or low dose of CTSD inhibitor pepstatinA (0.5ng/mL). Remarkably, both CTSD down-regulation approaches reduced HG-induced myocyte injury, as shown by elevated cleavage of Caspase3 and by propidium iodide staining. These results suggest that LMP and the ensuing CTSD expression mediate HG-induced cardiotoxicity. In addition, by using LMP/lysophagy reporter tfGalectin3, we found that HG-induced LMP was accompanied by impaired lysophagy, suggesting a failed elimination of damaged lysosomes by lysophagy, which may exacerbate HG-induced LMP. Indeed, the lysophagy inducer L-leucyl-L-leucine methyl ester (LLOMe) stimulated lysophagy flux, attenuated HG-induced LMP, and restored the beating frequency of HG-treated cardiomuyocytes. Together, these findings demonstrate a novel mechanism by which high glucose impairs lysophagy, induces LMP and triggers the release of CTSD, which collectively contribute to hyperglycemic cardiotoxicity.
High glucose–induced ROS activates TRPM2 to trigger lysosomal membrane permeabilization and Zn2+-mediated mitochondrial fission