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

Table 1 Principal modulators of iron metabolism involved in adenosine triphosphate-induced cell death

Gene	Function	Role in AICD	Effects of genetic deletion or overexpression	Ref.
P2RX7	Inflammation and immune regulation, neurotransmission, apoptosis and autophagy	Activates inflammatory mediators and increases calcium ions	Its activation is closely related to the development of cardiac diseases such as cardiomyopathy, myocardial infarction and myocarditis	[29]
CASP3	Execution stage of apoptosis	CASP3 cleavage by CASP1/4/5/11 forms pores, releasing proinflammatory cytokines	Caspase contributes to the progressive decline in systolic function observed in heart failure by facilitating the degradation of myofibrillar protein. Therefore, the selective inhibition of CASP3’s proteolytic function may offer a promising strategy for mitigating or reversing the effects of heart failure	[30]
PANX1	Widely involved in ATP and ion permeability, can effectively reduce CCI induced mechanical pain and thermal hyperalgesia	P2X7 activation opens PANX1 channels, releasing ATP and triggering cell death pathways	PANX1 channels release ATP, which then activates fibroblasts in the heart and promotes the development of cardiac fibrosis after myocardial infarction. PANX1 deficiency results in atrioventricular block, delayed ventricular depolarization, significantly prolonged QT interval and rate-corrected QT interval, and an increased incidence of atrial fibrillation following intraatrial burst stimulation	[25,31]
NLRP3	It plays an important role in inflammation and immune responses and can sense various stimuli inside and outside the cell	Upon activation by stimulatory signals, NLRP3 forms an inflammasome, triggering CASP1 activation. This in turn leads to the release of cytokines and apoptosis	Involved in the process of ischemia-reperfusion injury and endothelial dysfunction, affecting the changes of coronary blood flow; participate in chronic inflammatory response and myocardial hypertrophy, accelerate the production of pro-inflammatory cytokines, leading to the occurrence and development of heart failure	[16,19,20]
CASP1	Membrane hyperpolarization; mitochondrial depolarization and positive regulation of IL-1α production	CASP1 triggers the processing of cytokines, pyrosis, and inflammation, thereby orchestrating the inflammatory response	Involved in inflammation and loss of heart muscle cells. LVAD implantation may alter the inflammatory and apoptotic characteristics of the heart by regulating CASP1 expression levels. CASP1 deficiency resulted in more obvious myocardial hypertrophy in renal ischemia-reperfusion mice	[17,18]
P2RY1	Activates downstream signals	P2RY1 has the capacity to elevate calcium ion levels within the Golgi apparatus	P2RY1 gene is associated with the development of heart disease and the response to anticoagulant therapy. Meanwhile, the polymorphism of P2RY1 gene is associated with the onset age of myocardial infarction, which may have a protective effect or influence the progression of myocardial infarction	[32]
P2RY11	Immune regulation, neurotransmission, insulin secretion	It plays a role in immune inflammatory mechanisms	The P2RY11 gene is implicated in the regulation and repair of inflammatory processes in the heart. Enhanced expression of this gene may facilitate myocardial fibrosis and play a crucial role in the restoration of cardiac function following acute myocardial infarction	[20]
ORAI1	Calcium ion coupling is involved in the activation and proliferation of immune cells	Increased intracellular calcium ions	The ORAI1 gene plays an important role in the heart, especially in cardiac diseases such as cardiac hypertrophy and heart failure, and is involved in regulating the flow of calcium ions in cardiomyocytes, affecting the systolic and diastolic functions of the heart	[33]
STIM1	Calcium ion sensor. It is involved in immune cell activation, muscle contraction and cell cycle regulation	STIM1 responds to ATP-induced calcium influx by activating ORAI1, thereby contributing to cell death	STIM1 plays a pivotal role in regulating SOCE and Ca2+ storage replenishment, crucial for heart development and growth. Additionally, the STIM1 gene modulates energy substrate preferences in the heart, with implications for metabolic disorders like cardiac hypertrophy and diabetic cardiomyopathy. Elucidating its molecular mechanisms could lead to the discovery of novel therapeutic targets for the prevention and treatment of cardiac metabolic diseases	[23,24]
CASP8	Modulating apoptosis	CASP8 causes apoptosis	It is involved in apoptosis and cytokine processing and is crucial for heart development and hematopoietic function. Lack of CASP8 leads to defects in heart muscle development and a decrease in hematopoietic progenitor cells	[34]
CASP9	Modulating apoptosis (programmed cell death)	CASP9 causes apoptosis	The CASP9 gene is involved in mitochondria-mediated apoptosis in the heart. As an inhibitor of CASP9, HAX-1 protein protects cardiomyocytes from apoptosis and maintains cardiac function	[35]
CASP7	The executive stage of catalytic apoptosis	CASP7 causes apoptosis	Inhibition of CASP7 can reduce myocardial infarction size and apoptosis, providing a new strategy for the treatment of myocardial ischemia	[36]
P2RX3	Involved in the conduction of sensory neurons and the perception of pain	NA	It is involved in pain signal transduction caused by myocardial ischemia and is a potential therapeutic target	[37,38]
NLRP1	Regulates inflammation and immune response	Upon activation, NLRP1 triggers CASP1 activation, leading to the induction of pyroptosis and the release of IL-1β and IL-18	NLRP1 gene is closely related to cardiovascular diseases. The NLRP1 inflammatory complex expressed by NLRP1 gene is involved in the pathogenesis of cardiovascular diseases and may be a potential therapeutic target	[39]
P2RX4	Involved in cellular signaling	P2RX4 promotes AICD (pyroptosis) through the activation of the NLRP3 inflammasome, resulting in the production of IL-1β and IL-18	The P2RX4 gene in the heart may influence blood pressure and kidney function by regulating vascular tension	[40]
P2RX5	Involved in neurotransmission and pain regulation	NA	P2RX5 gene may be related to varicose veins and synaptic vesicles in the heart, and it is involved in cardiac development and functional regulation	[41]
SAPK	Involved in cellular stress response and inflammation regulation	ATP triggers cell death through SAPK pathways, modulating apoptosis, necrosis, and stress signaling mechanisms	It plays a role in regulating cardiomyocyte hypertrophy and apoptosis. MiR-350 induces cardiomyocyte hypertrophy by inhibiting the SAPK pathway, suggesting that the SAPK gene is a key regulator of pathologic heart hypertrophy and apoptosis	[42]
p38 MAPK	It is involved in cell signaling, cell stress response, inflammation regulation, apoptosis and other biological processes	ATP stimulates p38MAPK, ultimately leading to cell death via apoptosis and necrosis	It is involved in the regulation of cardiomyocyte proliferation, apoptosis and hypertrophy. Involved in the regulation of stress response and cardiomyocyte differentiation, its balance in terms of protective and deleterious effects affects cardiac function	[43]
ASK1	It regulates biological processes such as cell survival and death, inflammatory response, cell stress response, and oxidative stress	Elevated levels of ATP trigger cellular stress, activating ASK1 and subsequent downstream pathways, ultimately leading to cell death	ASK1 activation can lead to hypertrophy, fibrosis and dysfunction of the heart	[44]
NOX2	It plays a crucial role in the generation of reactive oxygen species within cells, thereby regulating physiological processes including cell signaling, immune response, and oxidative stress	ATP stimulates NOX2 activation, leading to ROS production, which induces oxidative stress and potentially triggers cell death	Increased NOX2 activity may lead to diaphragmatic dysfunction, which can trigger symptoms of heart failure	[45]
Bax	It is involved in regulating biological processes such as cell development, immune response and tumor suppression	Elevated levels of ATP trigger Bax activation, resulting in mitochondrial dysfunction and apoptotic cell death	It is involved in the process of myocardial apoptosis induced by ischemia	[46]
MLC	It plays a pivotal role in regulating muscle contraction and movement, thereby influencing biological processes including cell morphology and motility	Depletion of ATP impairs muscle contraction by compromising myosin function and cellular viability	Reduced MLC expression is associated with the pathogenesis of heart failure	[47]
ROCK I	It orchestrates biological processes encompassing cell morphology, polarity, and contraction, integral to functions like cell migration, muscle contractility, and cytoskeletal remodeling	ATP stimulates P2X7Rs, triggering apoptosis through the Rho/ROCK pathway, potentially involving ROCK I	It plays a vital role in signal transduction and regulation within cardiomyocytes; involvement in the regulation of Cav 3.2 channels and stabilization of HIF-1α may increase the risk of arrhythmia during ischemia	[48,49]
ERK1/2	It is involved in the regulation of biological processes such as cell growth, proliferation, differentiation and cell survival, and affects cell signaling and cell fate determination	ERK1/2 promotes cell survival and opposes apoptosis, yet sustained activation can ultimately trigger cell death. By activating the ERK1/2 pathway, it plays a pivotal role in determining cell fate	Signaling pathways involved in adaptive or adaptive remodeling; involved in cardiomyocyte hypertrophy and survival	[50,51]
P2X6	It is involved in the regulation of biological processes such as cell signaling, apoptosis and inflammatory response, and may play a role in neurotransmitter release and pain transmission	Activation may elevate calcium levels, potentially initiating cell death mechanisms	P2X6 gene is up-regulated in chronic heart failure, and its activation may be involved in the pathological process of chronic heart failure	[26]
CYTC	The electron transport molecules in the mitochondrial respiratory chain are involved in cellular respiration and energy production, as well as regulating the process of apoptosis	During cellular stress, the release of cytochrome c from mitochondria initiates the apoptotic process	Phosphorylation at Thr50 increases with aging, which can inhibit cardiomyocyte apoptosis, especially apoptosis caused by hypoxia/reoxidation, and protect cardiac function	[52]
TNF-α	It plays a crucial role in regulating biological processes encompassing inflammation, immune response, and apoptosis, thereby exerting significant influence on inflammatory conditions, immune disorders, and tumor progression	ATP triggers cell death by activating TNF-α and initiating apoptosis or necroptosis pathways. In response to ATP, immune cells produce TNF-α, thereby amplifying the cellular response	The TNF-α gene plays a key role in heart failure, promoting inflammation and cell damage. Increased expression of TNF-α in failing hearts correlates with disease severity and is a potential therapeutic target	[53]
P2RY5	It is involved in cell signaling, skin development, pigmentation and other biological processes, which may be related to hair follicle development and skin pigment distribution regulation	NA	In the heart, it may be associated with inflammation and Crohn’s disease activity index, and its expression level may be associated with cardiac dysfunction	[54]
P2RY14	It plays a pivotal role in regulating biological processes including immune and inflammatory responses, potentially contributing to the activation of immune cells and the release of inflammatory mediators	NA	P2RY14 gene may be involved in the inflammatory process of ischemic acute kidney injury in the heart, and its expression changes are related to the development of AKI after cardiac surgery, which may be a potential therapeutic target for preventing and alleviating ischemic AKI	[55]
P2RY13	It regulates cellular immune response, participates in the regulation of inflammatory response and immune cell activation, and plays a significant role in immune regulation and inflammatory processes	P2Y13 may play a significant role in ADP receptors, primarily implicated in maintaining ATP homeostasis	Variations in the P2RY13 gene are associated with cardiovascular risk markers that may affect heart health	[56]
P2RY12	It plays a crucial role in platelet aggregation, thrombosis, and hemostasis, thereby contributing significantly to blood coagulation and vascular repair processes	P2Y12 may play a role in ADP receptors, mainly involved in ATP homeostasis	The receptor encoded by the P2RY12 gene regulates platelet aggregation in the heart, preventing clots from forming. The use of P2Y12 inhibitors protects the heart and reduces the risk of myocardial infarction and reperfusion injury	[57]
P2RY6	It is integral to cell signaling and inflammation regulation, potentially contributing to the activation of immune cells and the secretion of inflammatory mediators	P2Y6 may play a role in calcium signaling processes	In hypertrophic cardiomyopathy, P2RY6 gene-associated lncRNAs exhibit significant upregulation and may regulate cardiac growth, serving as potential biomarkers and therapeutic targets for hypertrophic cardiomyopathy	[58]

AICD: Adenosine triphosphate-induced cell death; P2RX7: Purinergic receptor P2X7; CASP3: Caspase-3; PANX1: Pannexin-1; NLRP3: NOD-like receptor family pyrin domain-containing protein 3; CASP1: Caspase-1; P2RY1: P2Y purinoceptor 1; P2RY11: P2Y purinoceptor 11; ORAI1: Calcium release activated calcium channel protein 1; STIM1: Stromal interaction molecule 1; CASP8: Caspase-8; CASP9: Caspase-9; CASP7: Caspase-7; P2RX3: Purinergic receptor P2X3; NLRP1: NOD-like receptor family pyrin domain-containing protein 1; P2RX4: P2X purinoceptor 4; P2RX5: P2X purinoceptor 5; SAPK: Stress-activated protein kinase; p38 MAPK: p38 mitogen-activated protein kinases; ASK1: Apoptosis signal regulating kinase 1; NOX2: NADPH oxidase 2; Bax: BCL2 associated X; MLC: Myosin light chain; ROCK I: Rho-associated, coiled-coil containing protein kinase 1; ERK1/2: Extracellular signal regulated kinase 1 and 2; P2X6: P2X purinoceptor 6; CYTC: Cytochrome c; TNF-α: Tumor necrosis factor alpha; P2RY5: P2R purinoceptor 5; P2RY14: P2R purinoceptor14; P2RY13: P2R purinoceptor 13; P2RY12: P2R purinoceptor 12; P2RY6: P2R purinoceptor 6; ATP: Adenosine triphosphate; CCI: Chronic constriction injury; IL: Interleukin; NA: Not available; SAPK: Stress-activated protein kinase; ROS: Reactive oxygen species; TNF: Tumor necrosis factor; LVAD: Left ventricular assist device; HAX-1: Hematopoietic lineage substrate-1-associated protein X-1; MLC: Myosin light chain; HIF-1α: Hypoxia-inducible factor-1α; AKI: Acute kidney injury; lncRNA: Long noncoding RNA.

Table 2 Summary of small-molecule modulators in adenosine triphosphate-induced cell death-related diseases

Drug	Mechanism	Targets	Ref.
P2X7 antagonist	Inhibit P2RX7 function	High blood pressure; atherosclerosis	[79]
IL-1β and IL-18 inhibitors	Inhibit the release of IL-1β and IL-18	Myocardial infarction and heart failure	[79]
Caspase-3 inhibitors	Inhibit the proteolysis of caspase-3	Reduces or reverses heart failure	[30]
S-propranolol	Decreased caspase-3 activity	I/R injury	[80]
Spirolactone	Inhibits alpha-adrenergic vasoconstriction in the arteries	Drug-resistant hypertension	[81]
Prosulfanilone and carbenolone	Blocking thrombin-induced calcein outflow and reducing Ca2+ inflow, ATP release, platelet aggregation, and thrombosis at the in vitro arterial shear rate	Arterial thrombus	[82]
Curcumin, resveratrol, notoginseng lactone and allicin	Inhibition of NLRP3 inflammasome	Hypertension TOD	[63]
Pubescenoside A active compound	It inhibited NLRP3 inflammatory activation and induced Nrf2 signaling pathway	I/R injury	[83]
Resveratrol (PIC)	TG storage and caspase 1 activity were inhibited	Atherosclerosis
MRS-2179	Inhibit platelet aggregation	Thrombotic syndrome	[84,85]
MRS2500	Inhibit P2RY1	Thrombus	[86]
NF157	Inhibit inositol phosphate accumulation	I/R injury	[87]
SKF96365	The entry of orai1 Ca2+ was inhibited	Atherosclerosis	[88]
ML9	Inhibition of STIM1	Hypertrophy and Ca2+ overload due to I/R; cardiomyocyte death	[89]
TDCPP	Decreased STIM1 expression of and increased GSK3β phosphorylation	I/R injury	[90]
MMPSI	Selective inhibition of caspase 3/7	Myocardial ischemic injury	[36]
Acetyl-tyr-val-ala-asp chloromethyl ketone	They blocked caspase activation	Myocardial injury induced by ischemia and reperfusion; myocardial infarction	[91]
Hypericin	Up-regulation of autophagy after myocardial infarction	Myocardial infarction	[92]
MRS-2339	Activated the heart P2X receptor	Heart failure	[93]
Propofol	Induced autophagy	I/R injury	[94]
Carvedilol	Novel vasodilator beta-adrenergic receptor antagonist and potent antioxidant	Myocardial I/R induced apoptosis	[95]
Midazolam	Inhibit p38 MAPK	Myocardial I/R injury	[96]
Ulinastatin	Inhibit inflammation, oxidative stress and apoptosis	Chronic heart failure	[97]
Kaempferol	Inhibition of ASK1	Cardiac hypertrophy	[98]
KN-93	Inhibition of NOX2	Cardiac remodeling and heart failure	[99]
Acacetin	Inhibit oxidative stress, inflammation and apoptosis	Diabetic cardiomyopathy	[100]
CETP inhibitor	Elevated phosphorylation levels of vascular myosin light chain and myosin phosphatase target subunit 1, a protein that promotes contractility, along with enhanced reactive ROS production	Hypertension	[101]
Fasudil	ROCKI inhibition	Coronary vasospasm, angina pectoris, hypertension, heart failure	[102,103]
Isosteviol (STV)	ERK1/2 is selectively activated in cells exposed to stress	Myocardial ischemia-reperfusion	[103]
Adriamycin (DOX)	Induced oxidative stress	Heart failure	[105]
Plasminogen activator inhibitor 1	Release the pro-inflammatory cytokine TNF-α	Thromboembolism complication	[106]
Rosuvastatin	MG53 up-regulation was induced	Myocarditis	[107]
Na+/H+ exchanger 1	Catalyze increased intracellular Na uptake	Hypertrophy of heart; heart failure	[108]
Prasugrel	Inhibit P2RY12	ST-segment elevation myocardial infarction following primary percutaneous coronary intervention	[109]

P2RX7: Purinergic receptor P2X7; IL: Interleukin; I/R: Ischemia/reperfusion; ATP: Adenosine triphosphate; NLRP3: NOD-like receptor family pyrin domain-containing protein 3; TOD: Target organ damage; Nrf2: NF-E2-related factor-2; P2RY1: P2Y purinoceptor 1; STIM1: Stromal interaction molecule 1; GSK: Glycogen synthase kinase; MAPK: Mitogen-activated protein kinases; ASK1: Apoptosis signal regulating kinase 1; NOX2: NADPH oxidase 2; ROS: Reactive oxygen species; ROCK I: Rho-associated, coiled-coil containing protein kinase 1; ERK1/2: Extracellular signal regulated kinase 1 and 2; TNF: Tumor necrosis factor.