The role of the inflammasome and pyroptosis in heart failure

Abstract

Heart failure (HF) is a complicated clinical syndrome caused by abnormal cardiac structure and/or function, leading to ventricular filling and/or ejection dysfunction. Pyroptosis is a newly identified form of programmed cell death often accompanied by inflammation during HF. The NLRP3 inflammasome, acting as a caspase-1 activation platform, plays a critical role in the production of key pro-inflammatory cytokines and pyroptosis. Therefore, cell death and inflammasomes are involved in the pathophysiological process of HF. Our paper will review the latest research progress on the relationship among pyroptosis, inflammasomes, and HF.

Introduction

Heart failure, a chronic and progressively debilitating condition, continues to be a significant public health problem with a high rate of morbidity and mortality worldwide. At present, approximately one in 10 people aged 40 and over in the world will develop heart farilure (HF) with preserved ejection fraction (LVEF ≥50%) syndrome, which is the most common chronic cardiovascular disease, and there is no effective treatment thus far. ¹

Over the recent years, the understanding of heart failure pathophysiology has greatly evolved, shifting its understanding from a hemodynamic disorder to a more complex and multifactorial systemic disease. An emerging field of interest in this context is the role of inflammation and cell death, particularly the mechanism of a highly inflammatory form of programmed cell death known as pyroptosis. Inflammatory pathway is increasingly recognized as an important factor in the pathophysiology of HF. ² A recent study found the activation of inflammasome promotes the occurrence of chronic inflammation in HF patients, while probenecid can delay the progression of HF by reducing the activation of inflammasome. ³ Besides, the regulation of myocardial cell death also plays a crucial role in HF. Previous studies have shown that myocardial cell death patterns include apoptosis and necrosis. However, another new form of death, pyroptosis, plays an important role in the pathogenesis of HF. ⁴ Pyroptosis is a new form of programmed cell death that occurs earlier than apoptosis and is accompanied by the release of many proinflammatory factors during HF. ⁵ Therefore, cell death and inflammasomes are involved in the pathophysiological process of HF. This article will review the molecular and cellular mechanisms that underlie these processes, further illuminating our understanding of heart failure and paving the way for potential therapeutic interventions.

Role of inflammasomes in HF

An inflammasome is a multiprotein complex that leads to the activation of a pro-inflammatory caspase (e.g., caspase-1) and promotes the release of cytokines of the interleukin-1b (IL-1β) family. ⁶ The inflammasome is mainly composed of receptor proteins, apoptosis-associated speck-like protein containing card (ASC), and pro-caspase-1. At present, receptor proteins that can be assembled into inflammasomes have been identified, including Nucleotide oligomerization domain (NOD)-like receptors (NLRs) family members NLRP1, NLRP3, NAIP, and NLRC4. ⁷ Inflammasome-related cytokines are powerful molecules with multiple functions and can be widely and rapidly induced in both sterile and non-sterile inflammation. Although the acute activation of the inflammasome is essential for the host to resist infection, if the above reactions are overwhelming, they may also promote harmful effects. ⁸

Inflammatory mediators such as IL-1β, IL-6, or tumor necrosis factor -α (TNF-α) is considered a biomarker of HF. The increase of circulating pro-inflammatory cytokines is related to the impairment of cardiac function and the deterioration of prognosis in patients with HF. ⁹ In the recent Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), the efficacy of anti-IL-1β monoclonal antibody Canakinumab was evaluated for HF patients with a promising outcome. ¹⁰ The maturation and release of IL-1β are strictly realized through inflammasome. The activation of inflammasome is triggered by a series of pathogens or danger-related molecular patterns (DAMP), leading to the maturation of the caspase-1 enzyme, and finally cutting pro-IL-1β into a mature form. Studies have shown that the activation of inflammasome may play a role in various cardiovascular events. However, the role of inflammatory body activation in chronic heart disease such as HF is rarely studied. Luo et al ¹¹ found the circulating level of NLRP3 inflammatory corpuscles seems to be clinically related to cardiac function, NT-proBNP level, and cumulative rehospitalization rate at 6 months. Recently, Onódi et al ³ found that the expression of AIM2 inflammasome increased in the HF collected from human patients and animal models of chronic HF, emphasizing the importance of chronic inflammatory response under these conditions. In addition, increased expression of NLRC4 was also observed in human HF. They also found that the co-activation of multiple types of inflammasome is a possible phenomenon, which indicates that targeting a single type of inflammasome may not be the best strategy for cardiovascular diseases (including atherosclerosis and HF).

Role of pyroptosis in HF

Pyroptosis is a new type of programmed cell death found and confirmed in recent years. Its process is mediated by the inflammasome complex dominated by cysteine aspartate specific protein-1 (caspase-1), accompanied by the formation of cell membrane pores and the release of a large number of proinflammatory factors, inducing a cascading inflammatory response. ¹² The pyroptosis pathway includes the classical pathway and the nonclassical pathway. In the classical approach, pro-IL-1β And pro-IL-18 were cleaved by caspase-1 to form activated IL-1βand IL-18, full-length GSDMD is cut by caspase-1 and bound to the plasma membrane, resulting in cytoplasmic swelling. The plasma membrane breaks and releases pro-inflammatory cell contents. In the non-classical pathway, pyroptosis does not depend on caspase-1. GSDMD pore triggers the assembly of NLRP3 inflammasome and the maturation of caspase-1 and then activates caspase-1, which leads to the cleavage of IL-1βand IL-18. ⁴

At present, there are few studies on the specific mechanism of pyroptosis in the pathophysiology of heart failure. Yue et al ¹³ found that pyroptosis was associated with cardiac hypertrophy and heart failure by inducing cardiac hypertrophy in mice with aortic coarctation (TAC). They also found that after TAC or Ang II intervention, irisin normalized high levels of IL-1 β, cleaved, and GSDMD-N. In the mouse model, irisin alleviated TAC-induced myocardial hypertrophy and fibrosis and improved cardiac systolic function. Therefore, irisin can improve HF and myocardial hypertrophy by inhibiting pyroptosis. By establishing a sepsis mouse model, Wei et al ¹⁴ found that eugenol inhibited inflammation and pyroptosis through the estrogen receptor (ER) and Silent information regulator 1 (SIRT1) pathway, thereby reducing cardiac dysfunction caused by sepsis. Ni et al ¹⁵ established a rat model and a cardiomyocyte model of HF induced by isoproterenol (ISO), which were pretreated with echinacoside (ECH). They found that ECH effectively inhibited pyroptosis, down-regulated NOX2 and NOX4, decreased ROS levels, and improved cardiac function. In vitro, ECH reduces myocardial cell pyroptosis and inhibits NADPH/ROS/ER stress. They finally conclude that ECH can inhibit cardiac cell pyroptosis and improve cardiac function by inhibiting NADPH/ROS/ER stress. Zheng et al ¹⁶ found two new regulatory networks of competitive endogenous RNA (ceRNA) in HF through bioinformatics analysis. According to interaction and validation analysis, seven long-chain noncoding RNA (lncRNA) GAS5-mediated ceRNA regulatory pathways were speculated to affect programmed cell death, including seven cell apoptosis pathways, three iron death pathways, and one pyroptosis pathway. The results of this study provide new insights and potential research programs for further exploring the interaction between the ceRNA regulatory network and pyroptosis in HF in the future.

Interaction of pyroptosis and inflammasome in HF

HF is caused by cardiac remodeling due to heightened damage, cardiac injury due to pressure or volume overload, myocardial infarction, inflammatory cardiomyopathy, or idiopathic dilated cardiomyopathy. ¹³ HF often involves simultaneous activation of pyroptosis and inflammatory processes. ¹⁷ The increase of circulating pro-inflammatory cytokines is related to the impairment of cardiac function and the deterioration of prognosis in patients with HF. Inflammatory mediators such as interleukin-1b (IL-1b), interleukin-6, or tumor necrosis factor α (TNF-α) is considered as a biomarker of HF. ³ Inflammasome, as the activation platform of caspase, plays an important role in the occurrence of prognosis. When cells are stimulated differently, the induced pyroptosis pathway is different, which can be divided into caspase-1 dependent canonical pathway and caspase-4/5/11 dependent non-canonical pathway.^18,19 NLRP3 inflammasome pathway is the most common origin of pyroptosis and inflammation in HF. ²⁰

Mezzaroma et al ²¹ showed that myocardial cells formed NLRP3 inflammasome, whose activation eventually led to caspase-1-dependent cardiomyocyte death, called pyroptosis, but did not release IL-1 β. Wei et al ¹⁴ showed inhibition of NLRP3 inflammasome activation was associated with beneficial effects in sepsis-induced cardiac dysfunction, suppression of NLRP3 significantly reduced pyroptosis, and attenuated sepsis-associated myocardial injury. Zeng et al ²² found that NOX1 and NOX4 promote mitochondrion division mediated by Drp-1, increase ROS production and NLRP3 activation, and finally lead to myocardial pyroptosis. NLRP3 inflammasome-mediated cardiomyocyte pyroptosis induces and amplifies inflammation in dilated cardiomyopathy (DCM), eventually leading to myocardial dysfunction and HF. In contrast, inhibition of NOX1, NOX4, and Drp1 inhibited Dox-induced activation of NLPR3 inflammasome and pyroptosis. Besides, Dox-induced Drp1-mediated mitochondrion division and subsequent activation of NLRP3 inflammasome and pyroptosis were reversed by NOX1 and NOX4 inhibition. Mitochondrial dysfunction can induce mitochondrial DNA (mtDNA) to release and activate NLRP3 and melanoma-2 (AIM2). ²³ Blocking pyroptosis through AIM2 silencing can reduce fibrosis and protect heart function in diabetes mice, indicating the pathogenic role of pyroptosis in diabetes cardiomyopathy. In addition, oxidative stress induced by diabetes and the release of mtDNA into the cytoplasm can activate NLRP3 inflammasome and trigger myocardial cell pyroptosis, which plays a similar role in HF.^24,25

Recent studies have found that the activation of caspase-3 induced by Dox (a cardiotoxic anticancer drug that can induce cardiac cell death and HF) may trigger cardiac pyroptosis other than GSDME-dependent cardiac apoptosis. ²⁶ On the other hand, some studies have found that GSDMD mediated myocardial pyroptosis through NLRP3 inflammasome through doxorubicin-induced myocardial injury models in vitro and in vivo. ²⁷

Conclusion

The interaction between inflammasome and pyroptosis is emerging as two critical pathophysiological mechanisms contributing to the development of heart failure (HF). ²⁸ While the occurrence of inflammasome-mediated pyroptosis has been observed in various tissues and cell types, additional evidence is necessary to establish its definitive role in the progression and underlying mechanisms of certain heart diseases. ²⁹ Epidemiological studies have highlighted obesity, hypertension, and aging as key risk factors for HF, thus intensifying research efforts to investigate the crucial pathological involvement of inflammasome and pyroptosis in the pathogenesis of HF. ³⁰

Pyroptosis, a novel form of programmed cell death, has garnered attention in recent years due to its close association with the progression of inflammasome-related heart failure (HF). ³¹ A multitude of current studies have primarily concentrated on enhancing protein indicators and conducting pathological observations on pyroptosis and cardiac remodeling.^32–34 However, these investigations often lack in-depth exploration of the molecular interaction mechanisms, resulting in an unclear theoretical understanding, and subsequently, hinder the clinical translation of research findings. While the identification and confirmation of pyroptosis have laid a foundation for its potential role in HF, further research is essential to elucidate the intricate molecular pathways and key regulatory molecules involved in this process. Understanding the mechanisms underlying pyroptosis would not only shed light on the pathogenesis of HF but also pave the way for the development of novel therapeutic strategies targeting this cell death pathway. ³⁵

In summary, the molecular mechanisms underlying the interplay between inflammasome activation and pyroptosis in HF remain unclear. Research is needed to explore the specific molecular events that initiate these processes and their impact on cardiac dysfunction and remodeling. Understanding the role of inflammasome and pyroptosis in HF could potentially lead to the development of novel therapeutic interventions targeted at inhibiting or regulating these pathways, ultimately improving patient outcomes in HF Figures 1 and 2.

Figure 1.

Pathways related to inflammasome and potential targets.

Figure 2.

Pathways and possible targets of pyroptosis related to heart failure.