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Backgrounds: Inflammation underlies the mechanism of different kinds of heart disease. Cytoplasmic membrane localized N‐terminal fragment of gasdermin‐D (GSDMD‐N) could induce inflammatory injury to cardiomyocyte. However, effects and dynamic changes of GSDMD during the process of lipopolysaccharide (LPS) related inflammatory stress induced cardiomyocyte injury are barely elucidated to date. In this study, LPS related cardiomyocyte injury was investigated based on potential interaction of GSDMD‐N induced mitochondrial injury and mitophagy mediated mitochondria quality control. Methods: HL‐1 cardiomyocytes were treated with LPS and Nigericin to induce inflammatory stress. The dual‐fluorescence‐labelled GSDMD expressed HL‐1 cardiomyocytes were constructed to study the translocation of GSDMD. The mitochondrial membrane potential (MMP) was measured by JC‐1 staining. Mitophagy and autophagic flux were recorded by transmission electron microscopy and fluorescent image. Results: GSDMD‐N showed a time‐dependent pattern of translocation from mitochondria to cytoplasmic membrane under LPS and Nigericin induced inflammatory stress in HL‐1 cardiomyocytes. GSDMD‐N preferred to localize to mitochondria to permeablize its membrane and dissipate the MMP. This effect couldn't be reversed by cyclosporine‐A (mPTP inhibitor), indicating GSDMD‐N pores as alternative mechanism underlying MMP regulation, in addition to mitochondrial permeability transition pore (mPTP). Moreover, the combination between GSDMD‐N and autophagy related Microtubule Associated Protein 1 Light Chain 3 Beta (LC3B) was verified by co‐immunoprecipitation. Besides, mitophagy alleviating GSDMD‐N induced mitochondrial injury was proved by pre‐treatment of autophagy antagonist or agonist in GSDMD‐knock out or GSDMD‐overexpression cells. A time‐dependent pattern of GSDMD translocation and mitochondrial GSDMD targeted mitophagy were verified. Conclusion: Herein, our study confirmed a crosstalk between GSDMD‐N induced mitochondrial injury and mitophagy mediated mitochondria quality control during LPS related inflammation induced cardiomyocyte injury, which potentially facilitating the development of therapeutic target to myocardial inflammatory disease. Our findings support pharmaceutical intervention on enhancing autophagy or inhibiting GSDMD as potential target for inflammatory heart disease treatment. [ABSTRACT FROM AUTHOR]

Inflammation is an important process involved in several cardiovascular diseases (CVDs), and nod‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a vital player in innate immunity and inflammation. In this review, we aim to provide a comprehensive summary of the current knowledge on the role and involvement of NLRP3 inflammasome in the pathogenesis and treatment of CVDs. NLRP3 inflammasome functions as a molecular platform, and triggers the activation of caspase‐1 and cleavage of pro‐IL‐1β, pro‐IL‐18, and gasdermin D (GSDMD). Cleaved NT‐GSDMD forms pores in the cell membrane and initiates pyroptosis, inducing cell death and release of many intracellular pro‐inflammatory molecules. NLRP3 inflammasome activation is triggered via inter‐related pathways downstream of K+ efflux, lysosomal disruption, and mitochondrial dysfunction. In addition, the Golgi apparatus and noncoding RNAs are gradually being recognized to play important roles in NLRP3 inflammasome activation. Many investigations have revealed the association between NLRP3 inflammasome and CVDs, including atherosclerosis, ischemia/reperfusion (I/R) injury and heart failure induced by pressure overload or cardiomyopathy. Some existing medications, including orthodox and natural medicines, used for CVD treatment have been newly discovered to act via NLRP3 inflammasome. In addition, NLRP3 inflammasome pathway components such as NLRP3, caspase‐1, and IL‐1β may be considered as novel therapeutic targets for CVDs. Thus, NLRP3 inflammasome is a key molecule involved in the pathogenesis of CVDs, and further research focused on development of NLRP3 inflammasome‐based targeted therapies for CVDs and the clinical evaluation of these therapies is essential. [ABSTRACT FROM AUTHOR]