The role of pyroptosis in heart failure and related traditional chinese medicine treatments

Abstract

Pyroptosis is a type of programmed cell death that is mediated by both typical and atypical pathways and ultimately leads to the lysis and rupture of cell membranes and the release of proinflammatory factors, triggering an intense inflammatory response. Heart failure (HF) is a serious and terminal stage of various heart diseases. Myocardial hypertrophy, myocardial fibrosis, ventricular remodeling, oxidative stress, the inflammatory response and cardiomyocyte ionic disorders caused by various cardiac diseases are all risk factors for and aggravate HF. Numerous studies have shown that pyroptosis can induce and exacerbate these reactions, causing progression to HF. Therefore, targeting pyroptosis is a promising strategy to treat HF. This paper summarizes the role of pyroptosis in the development of HF and the underlying mechanism involved. Recent research progress on the ability of traditional Chinese medicine (TCM) extracts and formulas to inhibit pyroptosis and treat HF was summarized, and some traditional Chinese medicine extracts and formulas can alleviate different types of HF, including heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), and heart failure with midrange ejection fraction (HFmrEF), by targeting pyroptosis. These findings may provide new ideas and evidence for the treatment or adjuvant treatment of HF by targeting pyroptosis.

Keywords: botanical drug preparation; heart failure; mechanism; plant metabolites; pyroptosis; the NLRP3 inflammasome.

FIGURE 1

Classic and nonclassic pyroptosis pathways.

FIGURE 2

CFs are activated to form myofibroblasts (MFs) by a series of reactions involving NLRP3, leading to the development of myocardial fibrosis. (A) Extracellular ATP can stimulate P2X7 and NOX2 receptors, thereby mediating the production of intracellular ROS. (B) NF-κB is upregulated by ROS, and this upregulation promotes the expression of NLRP3 as well as the expression of pro-caspase-18 and pro-caspase-1β. (C) ROS stimulation induces the release of TXNIP from oxidized TRX, and TXNIP binds to the leucine-rich region of NLRP3, leading to inflammasome assembly. (D) The activation of NLRP3 triggers pyroptosis and the enhancement of the inflammatory response, thereby activating the profibrotic TGF-β/Smad signaling pathway. The Smad2-Smad3-Smad4 complex enters the nucleus, where it promotes the expression of collagen I and α-smooth muscle actin (α-SMA), leading to excessive deposition of type I collagen and ultimately resulting in myocardial fibrosis.

FIGURE 3

PLC is activated by extracellular ATP and hydrolyzes PIP2 in the cell membrane into DAG and IP3. IP3 is induced to interact with the IP3 receptor (IP3R) on the endoplasmic reticulum (ER) by DAG, leading to the efflux of Ca2+ stored in the ER into the cytoplasm. Moreover, SOCE channels are activated by extracellular ATP, and extracellular Ca2+ flows inward, leading to an increase in the intracellular cytoplasmic Ca2+ concentration. Excessive Ca2+ uptake leads to mitochondrial damage, including mitochondrial pore opening and rupture. The contents of mitochondria, including mtDNA and mtROS, are released and activate the NLRP3 inflammasome.