PANoptosis and cardiovascular disease: The preventive role of exercise training

1.1 Pyroptosis

Pyroptosis, a form of programmed cell death, is associated with an inflammatory response. It is a regulated process, and inhibiting it through regular training, medication or genetic methods can protect the heart under various conditions. Consequently, targeting pyroptosis could be a potential strategy for preventing cardiovascular disease. The discovery of pyroptosis has expanded our understanding of cell death in cardiovascular disease, revealing a new approach for its treatment and management. This review offers an update on the role of pyroptosis in cardiovascular disease and delves into the molecular pathways involved in the cardiovascular system [3]. Pyroptosis is initiated by the enzymatic activity of inflammatory proteases, specifically caspases, which lead to the rupture of the plasma membrane and the release of proinflammatory mediators and intracellular contents, such as interleukin-18 (IL-18) and interleukin-1 beta (IL-1beta). IL-1β and IL-18 significantly increase the risk of heart disease. Caspase-1-mediated pyroptosis results in cell destruction. Caspase-1 also triggers the production of anti-inflammatory cytokines, resulting in the degradation of proteins involved in inflammation. Inflammation stimulates the activation of caspase-1. The enzymatic processing of active caspase-1 and the active catalyst of IL-1β and precursor IL-18 (pro-IL-18) can be reduced by numerous antioxidant and anti-inflammatory drugs, supplements, training, and foods [4]. Ubiquitin-specific protease 14 (USP14) stabilizes nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) protein expression through deubiquitination, thereby facilitating endothelial cell pyroptosis in Coronary heart disease. miR-15b-5p restrains endothelial cell pyroptosis by targeting USP14 expression [5]. USP14 knockdown inhibits pyroptosis in cells by inducing ubiquitination of NLRP3, while overexpression of USP14 has the opposite effect, which is inhibited by the NLRP3 inflammasome inhibitor INF39 1 . USP14 exerts its positive regulatory effect on cell pyroptosis by modulating the NLRP3/Caspase-1/IL-1β and IL-18 signaling axes [6].

1.2 Apoptosis

Apoptosis is a specific form of programmed cell death that plays a crucial role in maintaining tissue homeostasis and development, as well as in tissue dysfunction. They are regulated by two types of genes that interact with each other: proapoptotic and antiapoptotic genes. The B-cell lymphoma-2 (Bcl-2) family includes antiapoptotic proteins such as Bcl-2 and B-cell lymphoma-extra large (Bcl-xL), which control mitochondrial dysfunction. In contrast, proapoptotic proteins such as Bcl-2-associated protein x (Bax), BCL2-interacting mediator of cell death (Bim), BCL2 associated agonist of cell death (Bad), and Bcl-2 interact to regulate the occurrence and progression of apoptosis, maintaining the balance between cell survival and cell death [4]. The upregulation of Bax expression inhibits Bcl-2 expression. The ratio of pro- to antiapoptotic proteins, such as Bax/Bcl-2, can influence the likelihood of cells undergoing apoptosis, regulate myonuclei and cell survival by controlling mitochondrial membrane stability, and change during the aging process. Studies have shown an increase in both Bcl-2 and Bax protein levels in aging rat cardiac muscle, as well as an increase in the Bax/Bcl-2 ratio and proapoptotic Bax and cleaved caspase-3 levels in aging and illness-related rat skeletal and cardiac muscles [7]. However, there was no significant difference in Bax and Bcl-2 protein expression levels during aging and illness, despite increased cardiomyocyte apoptosis. The mechanisms responsible for apoptotic signaling in aged hearts have several limitations. Apoptotic cell death involves pathways that activate caspase proteases, leading to the characteristic morphological changes associated with this type of cell death [8]. On other hand, the critical role Cyclophilin A, a pro-inflammatory factor that is involved in various cardiovascular diseases, plays in myocardial injury caused by oxidative stress-induced apoptosis, indicating that CypA can be a viable biomarker and a therapeutic target candidate formyocardial ischemia/reperfusion injury [9].

1.3 Necroptosis

In contrast, necroptosis was initially identified as a caspase-independent mode of cell death that can be initiated by Tumor necrosis factor (TNF) treatment only in the presence of a pancaspase inhibitor, such as zVAD, A pan-caspase inhibitor, fluoromethyl ketone [10]. Before this discovery, TNF was known to induce apoptosis by promoting protein interactions that lead to the activation of caspase 8; however, necroptosis necessitates the inhibition or disruption of caspase 8 function. Various upstream signaling components of apoptosis and necroptosis are common, and the sensitivity to each death pathway is regulated (sometimes in opposing manners) by a shared set of regulatory molecules, including the cellular Fas-associated death domain-like interleukin-1-β-converting enzyme-inhibitory protein (FLIP), the deubiquitinases A20 and cylindromatosis, and the cellular inhibitors of the apoptosis proteins cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein 2 (cIAP2) [11].

Additional death receptors and Toll-like receptors have been demonstrated to induce necroptosis, and intracellular triggers of necroptosis, such as DNA-dependent activator of IFN regulatory factors (DAI) and protein kinase R, were subsequently identified. The stimulation of the tumor necrosis factor receptor 1 (TNFR1) by TNF leads to signaling through the nuclear factor κB (NF-κB) pathway, which involves the polyubiquitination of receptor-interacting protein kinase 1 (RIPK1) and NF-κB essential modulator (NEMO) [12]. Upon deubiquitination of K63 and the linear ubiquitin chains of RIPK1 by deubiquitinases, RIPK1 loses its default prosurvival role and promotes cell death. TNFR1 recruits the adapter protein TNF-receptor–associated death domain (TRADD) to interact with the adapter Fas-associated death domain (FADD), which then binds to procaspase 8, a protease that is self-activated upon homodimer formation. Conversely, FLIP, a protein structurally similar to caspase 8 but lacking protease activity, forms a heterodimer that inhibits both caspase 8-mediated apoptosis and necroptosis. The caspase 8–FLIP heterodimer is prevalent in cells expressing FLIP and is induced upon NF-κB activation. Loss of either caspase 8 or FLIP or interference with their activation or function can lead to the initiation of necroptosis [13].

2.1 PANoptosis and MI

Myocardial infarction (MI) is characterized by a sudden interruption of blood flow to the heart muscle inducing a severe microcirculatory disorder associated with a significant decrease in oxygen supply, leading to the death of cardiomyocytes [20].

There is a growing understanding of the significant role that pyroptosis plays in the pathophysiology of MI. The hallmark of this form of programmed cell death is the cleavage of gasdermin D (GSDMD) and subsequent activation of caspase-1 [21–23]. This process results in the formation of pores in the cell membrane and the release of inflammatory cytokines such as IL-1β and IL-18. The inflammatory cascade that follows is critical because it amplifies inflammation and can impact plaque stability, both of which contribute to the increased risk of myocardial injury in MI [24]. Recent research has shed light on the importance of the inflammasome in this process, particularly the NLRP3 inflammasome, which detects stress signals and cellular damage, leading to the activation of caspase-1. The cleavage of GSDMD by caspase-1 not only induces cell death but also triggers the release of IL-1β and IL-18, attracting more immune cells to the site of injury, intensifying inflammation, and accelerating the progression of MI [25, 26].

The interruption of the blood supply to the myocardium during MI leads to ischemia and subsequent death of cardiomyocytes. Apoptosis contributes to the loss of these cells in the surrounding and ischemic core areas, impacting the size and severity of the infarct [27]. The molecular basis of apoptosis in MI involves a delicate balance between pro- and antiapoptotic signals within cardiac cells. Caspases are crucial for the execution phase of apoptosis, and their activation serves as a pro-apoptotic signal. Caspase activation in apoptosis results in Deoxyribonucleic Acid (DNA) damage and disruption of structural proteins in the cytoskeleton. The Bcl-2 protein family, which includes both apoptosis promoters and inhibitors, regulates these processes [28]. Additionally, myocardial apoptosis is exacerbated by ischemia–reperfusion injury, which occurs when blood flow to the tissue is restored following an ischemic period. This is due to the generation of reactive oxygen species and calcium overload, which activate apoptosis signaling pathways [29]. Conversely, antiapoptotic pathways, such as the Mitogen-activated Protein Kinase Kinase 1 – the extracellular signal-regulated proteinkinase 1/2 (MEK1-ERK1/2) signaling pathway, protect the heart from ischemic damage. Activation of this pathway can limit apoptosis by preventing DNA damage and preserving heart function during ischemia–reperfusion injury [30].

Necroptosis plays a critical role in the pathophysiology of MI, suggesting that targeting necroptosis could be a valuable therapeutic strategy. In animal studies, specific pharmacological inhibitors that target the receptor-interacting serine/threonine-protein kinase 1 (RIPK1), such as necrostatin-1, have been shown to reduce infarct size and myocardial cell death [31, 32]. Given that RIP1 is crucial to the necroptosis pathway, blocking the receptor-interacting serine/threonine protein kinase 1 (RIP1) has been demonstrated to maintain the structural integrity of the heart and prevent reactive fibrosis following myocardial ischemia/reperfusion [33]. Necroptosis is implicated in cardiovascular disorders beyond MI, with significant roles in diseases such as cardiac remodeling and vascular atherosclerosis. Therefore, focusing on necroptosis signaling pathways could have broad therapeutic implications for various cardiovascular conditions [34]. In conclusion, necroptosis represents a promising therapeutic target for MI, potentially leading to improved clinical outcomes by reducing overall myocardial damage and enhancing myocardial recovery post-MI through the inhibition of key molecules in the necroptosis process. Current research in this field aims to develop novel therapies for MI and other cardiovascular diseases in which necroptosis is involved. These findings underscore the importance of understanding necroptosis and its contribution to heart disease to guide the development of personalized treatments for individuals with cardiovascular conditions. The emerging link between PANoptosis and MI underscores the complex interplay of cell death pathways in cardiac injury, with the activation of these pathways post-MI potentially exacerbating myocardial damage and leading to adverse outcomes [35].

The PANoptosome, a vital molecular complex in PANoptosis, is significantly involved in MI, as its stimulation triggers inflammatory reactions and damage to heart muscle [36]. Additionally, there is an indication that focusing on PANoptosis elements such as inflammasomes could offer novel approaches for treating MI, potentially reducing heart muscle damage and enhancing cardiac function following an infarction [37]. This illustrates the potential of PANoptosis-targeted therapies in MI management, offering a distinct approach to alleviating the impacts of acute myocardial damage [38].

2.2 PANoptosis and HF

The frequency of heart failure (HF) varies from 1 to 3% in the general adult population, a condition characterized by the inability of the heart to effectively pump blood [3, 40].

Recent studies underscore the importance of early detection and targeted treatment methods in HF pathophysiology, with pyroptosis playing a significant role in the inability of the heart to pump blood efficiently enough to meet the body’s needs. GSDMD and Gasdermin E (GSDME) proteins create membrane pores, leading to cell lysis and swelling, as well as the release of proinflammatory cytokines such as IL-1β and IL-18 [24, 25]. These cytokines have been associated with the development of various cardiac diseases, including cardiac fibrosis and myocardial hypertrophy, and they also contribute to the inflammatory environment associated with HF. Myocardial hypertrophy, often occurring before HF, is a compensatory response to cardiac stress that is exacerbated by the inflammatory response triggered by pyroptosis. Specifically, IL-1β and IL-18 are known to attract more immune cells, which worsens inflammation and contributes to pathological remodeling [41]. The key components of cardiac remodeling, a process linked to the deterioration of cardiac function in HF, include cardiac fibrosis and hypertrophy. In addition to causing cardiomyocyte death, pyroptosis also induces excessive inflammation, leading to the accumulation of fibrotic tissue and myocardial hypertrophy, all of which contribute to this remodeling [42]. Mechanistically, two signaling pathways— one mediated by caspase-1 and the other by caspase-4/5/11— are the primary drivers of pyroptosis. When these caspases are activated, GSDMD and GSDME cleave and translocate to the cell membrane to create pores, resulting in cell death and the release of inflammatory substances [24].

Apoptosis is a critical factor in the death of cardiac myocytes in the context of HF and plays a significant role in the progression of this disease. The pathogenesis of HF is closely linked to the weakening of the myocardial wall, enlargement of the heart chambers, and decreased contractile ability resulting from the apoptosis of these cells [43]. Additionally, the key features of HF, such as ventricular dilatation and neurohormonal stimulation, may induce apoptosis by upregulating transcription factors that promote cell death. Cardiac remodeling, the heart’s response to damage and stress, involves structural changes, enlargement of myocardial cells, and an increase in apoptosis. This remodeling process is closely associated with the progression of HF, as the heart’s ability to contract effectively and maintain adequate blood flow is compromised by the loss of cardiomyocytes [44]. Recent research has suggested that inhibiting caspase inhibitor-induced apoptosis may improve HF symptoms and cell preservation both in vivo and in vitro. These inhibitors have the potential to halt the progression of HF by blocking the execution phase of apoptosis, leading to improved patient outcomes [45]. Given the complex pathophysiology of HF, a comprehensive understanding of apoptosis and its impact on cardiac function is essential. Identifying new therapeutic targets within the apoptotic pathway could enhance HF management and treatment, ultimately reducing the disease’s impact on patients’ quality of life. Necroptosis, characterized by the inability of the heart to effectively pump blood, is a significant contributor to HF development. RIPK1 and the receptor-interacting serine/threonine-protein kinase 3 (RIPK3) initiate this form of cell death, resulting in mixed lineage kinase domain-like) MLKL (phosphorylation and subsequent loss of plasma membrane integrity [46, 47].

The complex signaling pathways involved in the regulation of HF necroptosis are integral to molecular processes. For instance, Transforming growth factor-β-activated kinase 1 (TAK1), a critical protein that promotes the survival of cardiac cells, has been identified as a direct inhibitor of necroptosis and plays a role in myocardial remodeling and the control of myocardial homeostasis [34]. Furthermore, recent research has provided insight into the regulation of necroptosis in the heart and its significance in the pathogenesis of diseases such as MI and HF [48]. Necroptosis is implicated in the maintenance of myocardial homeostasis, cardiac remodeling and ischemia–reperfusion injury. Therefore, pharmaceutical strategies targeting necroptosis signaling pathways may be beneficial for the treatment of cardiovascular diseases, including HF. Necroptosis has also been found to exacerbate conditions such as sepsis-induced cardiomyopathy, underscoring the importance of this form of cell death in the progression of heart disease [49]. Ultimately, the distinct molecular pathways associated with necroptosis are linked to the remodeling and degeneration of the disease.

The correlation between PANoptosis and HF is complex, emphasizing the intricate interaction of cell death mechanisms in cardiac dysfunction. RNA-binding proteins, which are crucial for posttranscriptional gene control, have been associated with PANoptosis in HF, suggesting substantial involvement in the progression of this disease. The PANoptosome plays a role in different HF subtypes, each distinguished by varying pathway functions and levels of PANoptosis genes. This indicates that the disruption of PANoptosis may play a part in the onset and progression of HF, suggesting novel possibilities for the treatment and control of this complex condition [50].

2.3 PANoptosis and atherosclerosis

Atherosclerosis is a condition characterized by the accumulation of plaque in the arteries, posing a significant risk for heart-related issues. The development of atherosclerotic plaques involves inflammatory processes within the arterial wall [51].

Proinflammatory cytokines such as IL-18, IL-1β, and monocyte chemoattractant protein-1 are released during pyroptosis, accelerating the progression and instability of atherosclerotic plaques [52–54]. Inflammasomes, multiprotein complexes, play a crucial role in initiating pyroptosis and are linked to the inflammatory response in atherosclerotic plaques [55]. The activation of inflammasomes in macrophages and endothelial cells within plaques exacerbates plaque inflammation by producing proinflammatory cytokines. Gasdermin D is a key effector molecule in pyroptosis, and recent findings suggest that the GSDMD and GSDME proteins, which create pores in the mitochondrial and plasma membranes, are essential for pyroptosis [56]. These proteins not only stimulate the production of proinflammatory cytokines but also induce mitochondrial dysfunction, intensifying the proinflammatory response in atherosclerosis. Understanding these molecular pathways opens up possibilities for therapeutically targeting pyroptosis to manage inflammation and potentially slow the progression of atherosclerosis [57]. Moreover, oxidized low-density lipoprotein (LDL) cholesterol may be released from atherosclerotic plaques when macrophages undergo pyroptosis [58]. The cholesterol that is released can exacerbate lipid accumulation in the artery wall, leading to oxidative stress [59] and perpetuating the cycle of inflammation and plaque formation [60]. Endothelial cell pyroptosis can also compromise the structural integrity of the vascular wall, increasing the risk of thrombosis and plaque rupture [61].

Apoptosis plays a role in removing macrophages from atherosclerotic plaques. Macrophages are crucial for atherosclerosis development due to their ability to metabolize fats and generate foam cells [62]. These foam cells may undergo apoptosis and contribute to the necrotic cores of atherosclerotic plaques [63]. Vascular smooth muscle cells in atherosclerotic lesions may also undergo apoptosis, potentially weakening the fibrous cap of a plaque and increasing the chances of rupture [64]. Ruptured plaques can trigger thrombotic events such as heart attacks or strokes. Chemokines and cytokines released by apoptotic cells attract immune cells to sites of cell death. The infiltration of immune cells into atherosclerotic plaques has the potential to increase inflammation, thereby worsening plaque instability [65].

Atherosclerotic progression has been associated with necroptosis, a form of regulated necrosis. Necroptosis is more proinflammatory and caspase-independent than apoptosis. It affects smooth muscle cells, macrophages, and vascular endothelial cells within atherosclerotic plaques, contributing to plaque instability. The phosphorylation of mixed lineage kinase domain-like protein and RIPK3 is a key biochemical process underlying the necroptosis of pseudokinase MLKL. It is well established that atherogenic lipoproteins, particularly LDL, can transcriptionally cause the phosphorylation of RIPK3 and MLKL. These are crucial steps in the necroptotic process [66]. Furthermore, the formation of the necrotic core and the progression of plaque have been linked to necroptosis in human atherosclerotic tissues [67]. Macrophages are a primary target for therapeutic interventions aimed at reducing the burden of atherosclerosis, as they play a crucial role in inflammation and necroptosis within plaques [68]. Macrophages infiltrate the vascular intima, activate endothelial cells, and recruit monocytes to the vessel wall. These monocytes differentiate into macrophages, ingesting modified lipoprotein to form foam cells [69]. These foam cells undergo apoptosis and necrosis, leading to plaque destabilization and rupture. Macrophages further contribute to lesion inflammation through cytokine secretion and proteolytic activity, resulting in atherothrombosis and ischemic events [70]. These findings highlight the potential of necroptosis as a novel target for therapeutic intervention and as a biomarker for the progression of atherosclerosis [71].

PANoptosis facilitates communication and mutual regulation among different pathways of cell death, both of which play crucial roles in the progression of atherosclerotic disease [72]. An example of this is the AIM2 inflammasome, which has been shown to adjust innate immune sensors and initiate inflammatory signaling, thereby contributing to the inflammatory environment of atherosclerosis [73]. Moreover, the combination of molecules from pyroptotic, apoptotic, and necroptotic pathways leads to the formation of the PANoptosome, which is activated by various pathogenic events, including those associated with atherosclerosis [74]. This complex interplay of cell death pathways in PANoptosis underscores the multifaceted nature of atherosclerosis, which is characterized as both a lipid-storage disorder and an inflammatory state [75].

3.1 Pyroptosis and training

In general, it has been shown that exercise can prevent cell death [3, 76] and Cardiovascular Disease [40, 77]. In recent years, several studies have demonstrated the significance of pyroptosis in the development of atherosclerosis [78]. The NLRP3 inflammasome plays a crucial role in driving atherosclerosis [79]. Various risk factors, including oxidative stress, hyperglycemia, dyslipidemia, inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress, can trigger the activation of the NLRP3 inflammasome [80]. By inhibiting or reversing these risk factors, it is possible to suppress overactivation of the NLRP3 inflammasome and consequently inhibit pyroptosis. Research indicates that exercise has the potential to decrease cardiac oxidative stress and the expression of the NLRP3 inflammasome in ApoE-/- mice. Lee et al. discovered that exercise training could reduce the increased expression of NLRP3 and its downstream factors in an obese mouse model [81]. Moreover, in a diabetic mouse model, exercise was able to restore the expression of endothelial nitric oxide synthase (eNOS) and the production of nitric oxide (NO) by reducing NLRP3 expression, thereby preventing the downstream effects of NLRP3 activation [82]. Nevertheless, it remains uncertain whether aerobic exercise can effectively inhibit NLRP3 inflammasome-mediated pyroptosis in the aorta [78].

3.2 Apoptosis and training

The expression of the Bcl-2 gene in the ventricular muscles of trained animals did not significantly increase compared to that in the ventricular muscles of control animals (11%) [83]. However, the transcript content of the Bcl-2 gene was 48% and 35% greater in the soleus and ventricle samples, respectively, of trained animals than in the muscles of control animals, indicating that running 5 days weekly for 8 weeks attenuates the extent of apoptosis in cardiac and skeletal muscles [84]. Furthermore, running 5 days weekly for 12 weeks led to a downregulation of caspase-9 (Bcl-2 family) levels in left ventricle samples from both the young and old age groups [85]. Additionally, Bcl-2 protein levels decreased after spontaneous exercise in the muscles of mdx mice [86]. These findings suggest that Bcl-2 expression does not consistently respond to physical exercise in the same manner. Previous research has shown an increase in both the Bcl-2 and Bax protein levels in aging rat cardiac muscle [87]. Other studies have also reported an increase in Bax and Bax/Bcl-2 ratio protein levels in aging rat cardiac muscle [13], as well as in pro-apoptotic Bax and cleaved caspase-3 levels and DNA fragmentation in aging rat skeletal and cardiac muscles [88, 89]. However, there was no significant difference in the Bax and Bcl-2 protein expression levels during aging, even with increased cardiomyocyte apoptosis [90]. The nonsignificant decrease in pro-apoptotic Bax gene expression after training in young and old cardiac muscles is not in line with previous studies. Compared with that in control animals, the transcript content of Bax in the soleus muscles of trained animals decreased significantly by 35% [84]. Running 5 days weekly for 12 weeks also resulted in a significant decrease in Bax protein expression in the left ventricle in the older trained group compared with that in the older control group [85]. The transcript levels of Bax in the ventricular muscles of trained animals did not significantly differ from those of control animals [91].

3.3 Necroptosis and training

Necroptosis, a type of regulated necrotic cell death, has emerged as a potential molecular target for cardiovascular diseases, particularly age-related heart disease [92]. The atrial fibrillation (AF) is an age-related arrhythmia, and its prevalence increases with age. We demonstrated that necroptosis was stimulated in Calcium Chloride – acetylcholine (CaCl2-Ach) -induced AF mice and that the inhibition of necroptosis via the necrostatins like necrostatin-1 (Nec-1) attenuated the AF burden and atrial structural remodeling, indicating the critical role of necroptosis in AF pathogenesis [93]. Similarly, we found increased AF susceptibility and atrial fibrosis in obese mice and decreased AF susceptibility and atrial fibrosis after Nec-1 administration, further supporting the requirement of necroptosis for AF pathogenesis independent of AF models [10]. These findings are consistent with previous reports showing the crucial role of necroptosis and downstream targets in fibrosis, a hallmark of AF. For example, Lee et al. revealed that necroptosis is involved in the pathogenesis of lung fibrosis and that RIP3 knockout and RIP1 knockout are involved [94].

The mechanistic connection between necroptosis and atrial remodeling or cardiovascular disease (CVD) and atrial fibrillation (AF) pathophysiology has been extensively investigated. On the one hand, the compensatory proliferation of fibroblasts may be triggered in response to the loss of cardiomyocytes due to necroptosis to preserve tissue homeostasis. On the other hand, necroptotic cells can release cellular contents, leading to inflammatory [95] and fibrotic responses, ultimately resulting in the development of myocardial fibrosis in severe cardiac pathological conditions. A growing body of evidence indicates the presence of inflammation and fibrosis in patients with CVD and AF, as well as in experimental models of CVD and AF, such as CaCl2-Ach-induced CVD and AF and HFD-induced AF [96]. Therefore, necroptosis, along with the subsequent activation of inflammation and fibrosis, may serve as a crucial pathogenic factor in CVD and AF. Notably, the upregulation of necroptosis, coupled with the chronic activation of inflammation and fibrosis, is frequently observed in elderly individuals, suggesting that necroptosis could be a mechanism underlying age-related diseases such as CVD and AF and suggesting a potential therapeutic target for the prevention and management of CVD and AF in elderly individuals. In addition to inflammation and fibrosis, metabolic syndrome, including insulin resistance, is also commonly implicated in the pathogenesis of CVD and AF [97].

On the one hand, the compensatory proliferation of fibroblasts may be triggered in response to the loss of cardiomyocytes due to necroptosis to maintain tissue homeostasis. Conversely, necroptotic cells can release cellular contents, leading to inflammatory and fibrotic responses and ultimately resulting in the development of myocardial fibrosis in severe cardiac pathological conditions. There is a growing body of evidence indicating the presence of inflammation and fibrosis in patients with AF and in experimental AF models such as CaCl2-Ach-induced AF and HFD-induced AF [98]. Therefore, necroptosis, along with the activation of inflammation and fibrosis, could be a significant pathogenic factor in AF. Notably, the upregulation of necroptosis, coupled with the chronic activation of inflammation and fibrosis [99], is commonly observed in elderly individuals, suggesting that necroptosis may be a potential mechanism for age-related diseases such as AF, offering a potential therapeutic target for AF prevention and management in elderly individuals. In addition to inflammation and fibrosis, metabolic syndrome, including insulin resistance, is also frequently implicated in the pathogenesis of AF [10]. Polina et al. and Maria et al. demonstrated the role of insulin signaling in AF development in type 1 diabetes [100]. It is widely acknowledged that exercise serves as a form of medicine for cardiovascular diseases. Research by Hou et al. showed that high-intensity swim training for 4 weeks protected against myocardial ischemia/reperfusion injury and induced mild cardiac hypertrophy in rats [98]. Similarly, Wang et al. revealed that moderate-intensity swim training for 3-9 weeks improved heart function and reduced cardiac hypertrophy and fibrosis in heart failure mice [101]. However, the relationship between exercise and AF appears to be more complex. Aschar-Sobbi et al. reported that 6 weeks of high-intensity swim training did not have a significant impact on AF [102].

Several studies have indicated that exercise plays a role in reducing cardiac apoptosis and necrosis. High-intensity interval training (HIIT) has been previously demonstrated to prevent cardiac remodeling after myocardial ischemia/reperfusion injury by targeting necroptosis [103]. Three weeks of swim exercise training inhibited necroptotic signaling in CaCl2-Ach-induced AF mice. This raises the question of how exercise inhibits necroptotic signaling. Previous research has suggested that oxidative stress and Adenosine monophosphate-activated protein kinase (AMPK) are upstream mechanisms that regulate necroptosis and that autophagy is linked to necroptosis. Therefore, activated autophagy after exercise may lead to decreased necroptosis in AF mice. A deeper understanding of the molecular mechanisms involved can help identify potential targets for exercise-induced cardioprotection and uncover new therapeutic strategies for AF prevention and treatment [10].