Molecular and metabolic landscape of adenosine triphosphate-induced cell death in cardiovascular disease

Abstract

The maintenance of intracellular and extracellular adenosine triphosphate (ATP) levels plays a pivotal role in cardiac function. In recent years, burgeoning attention has been directed towards ATP-induced cell death (AICD), revealing it as a distinct cellular demise pathway triggered by heightened extracellular ATP concentrations, distinguishing it from other forms of cell death such as apoptosis and necrosis. AICD is increasingly acknowledged as a critical mechanism mediating the pathogenesis and progression of various cardiovascular maladies, encompassing myocardial ischemia-reperfusion injury, sepsis-induced cardiomyopathy, hypertrophic cardiomyopathy, arrhythmia, and diabetic cardiomyopathy. Consequently, a comprehensive understanding of the molecular and metabolic underpinnings of AICD in cardiac tissue holds promise for the prevention and amelioration of cardiovascular diseases. This review first elucidates the vital physiological roles of ATP in the cardiovascular system, subsequently delving into the intricate molecular mechanisms and metabolic signatures governing AICD. Furthermore, it addresses the potential therapeutic targets implicated in mitigating AICD for treating cardiovascular diseases, while also delineating the current constraints and future avenues for these innovative therapeutic targets, thereby furnishing novel insights and strategies for the prevention and management of cardiovascular disorders.

Keywords: Adenosine triphosphate induced cell death; Cardiovascular diseases; Metabolic pathways; Molecular mechanisms; Myocardial ischemia-reperfusion injury.

Figure 1

Regulation mechanism of adenosine triphosphate homeostasis and adenosine triphosphate-induced cell death. A: P2 receptor activation pathway; B: Ca²⁺ pathway induces cell death pathways; C: The induction of cell death by adenosine triphosphate results in the release of immune inflammatory factors and activation of immune pathways that further promote cell death; D: The concurrent depletion of mitochondrial membrane potential, disruption of mitochondrial integrity, generation of reactive oxygen species, and alterations in mitochondrial membrane permeability jointly contribute to the ultimate demise of the cell. ATP: Adenosine triphosphate; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; PNAX1: Pannexin-1; GSDMD: Gasdermin D; NLRP3: NOD-like receptor family pyrin domain-containing protein 3; IL: Interleukin; ACS: Apoptosis-associated speck-like protein containing a caspase recruitment domain; ORAI1: Calcium release activated calcium channel protein 1; STIM1: Stromal interaction molecule 1; CYTC: Cytochrome c; APAF1: Apoptotic protease-activating factor 1; HMGB: High-mobility group box; TNF: Tumor necrosis factor; TIMP1: Tissue inhibitor of matrix metalloprotease 1; MMP: Matrix metalloproteinase; TGF: Transforming growth factor; NF-κB: Nuclear factor κB; STAT: Signal transducer and activator of transcription; MYD88: Myeloid differentiation factor-88; TRAF2: Tumor necrosis factor receptor associated factor 2; TAK1: Beta-activated kinase 1; JNK: c-Jun N-terminal kinase; MAP3K5: Mitogen-activated protein kinase kinase kinase 5; IRAK: Interleukin-1 receptor-associated kinase; MAF-C: MAF BZIP transcription factor C; NOS2: Nitric oxide synthase; ROS: Reactive oxygen species; mTPT: Mitochondrial permeability transition.