GSDMD-mediated pyroptosis promotes cardiac remodeling in pressure overload

ABSTRACT

Background

Gasdermin D (GSDMD) forms membrane pores to execute pyroptosis. But the mechanism of how cardiomyocyte pyroptosis induces cardiac remodeling in pressure overload remains unclear. We investigated the role of GSDMD-mediated pyroptosis in the pathogenesis of cardiac remodeling in pressure overload.

Methods

Wild-type (WT) and cardiomyocyte-specific GSDMD-deficient (GSDMD-CKO) mice were subjected to transverse aortic constriction (TAC) to induce pressure overload. Four weeks after surgery, left ventricular structure and function were evaluated by echocardiographic, invasive hemodynamic and histological analysis. Pertinent signaling pathways related to pyroptosis, hypertrophy and fibrosis were investigated by histochemistry, RT-PCR and western blotting. The serum levels of GSDMD and IL-18 collected from healthy volunteers or hypertensive patients were measured by ELISA.

Results

We found TAC induced cardiomyocyte pyroptosis and release of pro-inflammatory cytokines IL-18. The serum GSDMD level was significantly higher in hypertensive patients than in healthy volunteers, and induced more dramatic release of mature IL-18. GSDMD deletion remarkably mitigated TAC-induced cardiomyocyte pyroptosis. Furthermore, GSDMD deficiency in cardiomyocytes significantly reduced myocardial hypertrophy and fibrosis. The deterioration of cardiac remodeling by GSDMD-mediated pyroptosis was associated with activating JNK and p38 signaling pathways, but not ERK or Akt signaling pathway.

Conclusion

In conclusion, our results demonstrate that GSDMD serves as a key executioner of pyroptosis in cardiac remodeling induced by pressure overload. GSDMD-mediated pyroptosis activates JNK and p38 signaling pathways, and this may provide a new therapeutic target for cardiac remodeling induced by pressure overload.

KEYWORDS:

• Gasdermin D (GSDMD)
• pyroptosis
• pressure overload
• transverse aortic constriction (TAC)
• cardiac remodeling

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Health Science and Technology Project of Shanghai Pudong New Area Health Commission (PW2019A-13), the National Natural Science Foundation of China (81500191), the Health Science and Technology Project of Jiangxi Province (SKJP220210327), and Top-level Clinical Discipline Project of Shanghai Pudong District Grant (PWYgf2021-01). Shanghai Key Clinical Specialty Project (shslczdzk06202)