Cardiac Remodeling in Heart Failure: Role of Pyroptosis and Its Therapeutic Implications

Abstract

Pyroptosis is a kind of programmed cell death closely related to inflammation. The pathways that mediate pyroptosis can be divided into the Caspase-1-dependent canonical pathway and the Caspase4/5/11-dependent non-canonical pathway. The most significant difference from other cell death is that pyroptosis rapidly causes rupture of the plasma membrane, cell expansion, dissolution and rupture of the cell membrane, the release of cell contents and a large number of inflammatory factors, and send pro-inflammatory signals to adjacent cells, recruit inflammatory cells and induce inflammatory responses. Cardiac remodeling is the basic mechanism of heart failure (HF) and the core of pathophysiological research on the underlying mechanism. A large number of studies have shown that pyroptosis can cause cardiac fibrosis, cardiac hypertrophy, cardiomyocytes death, myocardial dysfunction, excessive inflammation, and cardiac remodeling. Therefore, targeting pyroptosis has a good prospect in improving cardiac remodeling in HF. In this review, the basic molecular mechanism of pyroptosis is summarized, the relationship between pyroptosis and cardiac remodeling in HF is analyzed in-depth, and the potential therapy of targeting pyroptosis to improve adverse cardiac remodeling in HF is discussed, providing some ideas for improving the study of adverse cardiac remodeling in HF.

Keywords: cardiac fibrosis; cardiac remodeling; heart failure; inflammation; pyroptosis.

Figure 1

The basic molecular mechanism of pyroptosis. The canonical pathway of pyroptosis, Nod-like receptors protein-3 (NLRP3), NLRP1, NLRP6, NLRP9, absent in melanoma 2 (AIM2), and Pyrin binds to the N-terminal PYD region of the apoptosis-associated speck-like protein (ASC) to activate ASC proteins through protein-protein interactions. The C-terminal CARD domain of ASC and the N-terminal CARD domain of pro-Caspase-1 combine to recruit active-Caspase-1. The binding complex of PRRs, ASC, and pro-Caspase 1 is termed the inflammasome. On the one hand, Caspase-1 recognizes pro-IL-1β and pro-IL-18, converts them into IL-1β and IL-18, and releases them extracellular to expand the inflammatory response, on the other hand, Caspase-1 shear Gasdermin family protein GSDMD to separate its N- and C- domains, N-terminal fragments are released to the membrane, mediating the formation of cell membrane pores, releasing inflammatory factors and inducing pyroptosis. NLRC4 can directly interact with pro-Caspase-1 via CARD-CARD to form active-Caspase-1 and induce pyroptosis. The non-canonical pathway of pyroptosis, Caspase4/5/11 can directly bind to lipopolysaccharide (LPS) in the cytoplasm and initiate pyroptosis following cleavage of GSDMD-induced membrane pore formation and subsequent cell membrane rupture. The K⁺ efflux caused by cell membrane pore formation induces activation of the NLRP3/ASC/ Caspase-1 pathway. In addition, Caspase-3 cleaves the Gasdermin family protein GSDME, releasing the N-terminal active fragment to the cell membrane, leading to pyroptosis.

Figure 2

Role of pyroptosis in cardiac remodeling. Pyroptosis causes cardiac fibrosis, cardiac hypertrophy, cardiomyocytes death, myocardial dysfunction, excessive inflammation, and cardiac remodeling in heart failure.