Adenosine triphosphate-induced cell death in heart failure: Is there a link?

Abstract

Heart failure (HF) has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology. Adenosine triphosphate (ATP)-induced cell death represents a novel form of regulated cell deaths, marked by cellular energy depletion and metabolic dysregulation stemming from excessive ATP accumulation, identifying its uniqueness compared to other cell death processes modalities such as programmed cell death and necrosis. Growing evidence suggests that ATP-induced cell death (AICD) is predominantly governed by various biological pathways, including energy metabolism, redox homeostasis and intracellular calcium equilibrium. Recent research has shown that AICD is crucial in HF induced by pathological conditions like myocardial infarction, ischemia-reperfusion injury, and chemotherapy. Thus, it is essential to investigate the function of AICD in the pathogenesis of HF, as this may provide a foundation for the development of targeted therapies and novel treatment strategies. This review synthesizes current advancements in understanding the link between AICD and HF, while further elucidating its involvement in cardiac remodeling and HF progression.

Key Words: Heart failure; Adenosine triphosphate-induced cell death; Cardiomyopathy; Myocardial ischemia-reperfusion injury; Ejection fraction retention; Non-myocardial

Core Tip: Heart failure has become a significant worldwide health threat due to its complex pathophysiology and multifactorial causes. Adenosine triphosphate (ATP)-induced cell death is a newly recognized form of regulated cell death, distinct from apoptosis and necrosis, characterized by energy depletion and metabolic disturbances resulting from excessive ATP accumulation. Recent studies indicate that ATP-induced cell death (AICD) is primarily regulated by biological processes involving energy metabolism, redox balance, and intracellular calcium regulation. AICD is vital in heart failure, particularly in situations such as myocardial infarction, ischemia-reperfusion injury, and chemotherapy. Investigating its role in heart failure pathogenesis could provide insights into new therapeutic strategies. This review summarizes recent findings on the link between AICD and heart failure, highlighting its impact on cardiac remodeling and disease progression.

INTRODUCTION

Heart failure (HF) is a pivotal worldwide health concern characterized by complex pathophysiological processes and multiple contributing factors[1], which has become a leading threat to public health worldwide because of its intricate pathophysiological mechanisms and multifactorial etiology. HF is a multifaceted syndrome marked by morphological or operational impairment, bringing about inadequate oxygen delivery to meet the body's metabolic needs[2]. It is estimated that the burden of HF in the global adult population is 1%-2%, which sharply increases to about 10% among the population aged 75 and above[3].This trend is anticipated to continue in the future. Nonetheless, the prognosis of patients diagnosed with HF is still far from favourable; up to 50% of them will be dead within 5 years, and among those admitted to hospital with HF, after 1 year, 40% of them will either be dead or have another admission[4]. Adenosine triphosphate (ATP)-induced cell death is a distinct type of controlled cell demise characterized by energy depletion and metabolic dysregulation caused by excessive ATP buildup[5], which sets it apart from other forms of cell deaths like necrosis and apoptosis[6]. Understanding the distinct mechanisms and effects of ATP-induced cell death (AICD) is crucial for gaining insights into its roles in both physiological and pathological contexts. There is increasing evidence indicating that cell deaths triggered by ATP are mainly regulated through different biological pathways such as energy metabolism, redox homeostasis and intracellular calcium balance[7], which play crucial roles in determining the destiny of cells exposed to AICD[8]. Recent studies have demonstrated that AICD plays a critical role in HF triggered by pathological stimuli such as myocardial infarction (MI), ischemia-reperfusion injury (IRI) and chemotherapy[9]. Thus, it is essential to investigate the function of AICD in the pathogenesis of HF, as this may lay the groundwork for targeted therapies and innovative treatments[10]. This review discusses recent progresses in exploring the relationship between AICD and HF, along with their functions in cardiac remodeling and the advancement of HF, aiming to provide insights into the mechanisms underlying AICD and their impact on the process of HF, with the focus on myocardial structural remodeling.

AICD SIGNALING

AICD manifests as apoptosis or necrosis, characterized by distinct morphological and biochemical features influenced by factors like cell type, ATP concentration and environmental conditions. Apoptosis involves cellular shrinkage, the decline of connectivity, disruption of mitochondrial membrane potential, cytochrome C (CYTC) release, nucleolar fragmentation and DNA degradation into fragments of 180-200 base pairs. Apoptotic bodies are formed without triggering inflammation, as they are engulfed by phagocytes. Conversely, necrosis is marked by increased membrane permeability, cellular swelling, organelle deformation, eventual rupture and inflammatory responses. Tissue healing post-necrosis often leads to fibrosis and scar formation. The mode of ATP-induced deaths depends on cumulative cellular and environmental factors (Figures 1, 2, 3 and 4), mainly including: (1) Activation of membrane-bound purinergic P2 receptors; (2) Induction of cell death pathways via the Ca²⁺ pathway; (3) Release of immune-inflammatory mediators activating immune pathways; and (4) Mitochondrial dysregulation, including loss of membrane potential, integrity disruption, reactive oxygen species (ROS) production, and shifted membrane permeability, collectively leading to cell death[11-17].

Figure 1 P2 receptor activation pathway. ATP: Adenosine triphosphate; ADP: Adenosine diphosphate; P2RX: Purinoceptor receptor P2X; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; NLRP1: NLR family pyrin domain-containing protein 1; IL-1β: Interleukin-1 beta; Pro-IL-1β: Pro-forms of Interleukin-1 beta; PANX1: Pannexin 1; N-GSDMD: N-Gasdermin D; GSDMD: Gasdermin D. Drawn by Figdraw.

Figure 2 Ca²⁺ pathway induces cell death pathways. ATP: Adenosine triphosphate; P2RX: Purinoceptor receptor P2X; ORAI1: Calcium release-activated calcium channel protein 1; PANX1: Pannexin 1; STIM1: Stromal interaction molecule 1; CYTC: Cytochrome C; APAF1: Apoptotic protease-activating factor 1. Drawn by Figdraw.

Figure 3 Adenosine triphosphate triggers the release of immune-inflammatory factors from cells, activating immune pathways. ATP: Adenosine triphosphate; HMGB1: High mobility group box-1 protein; TNF: Tumor necrosis factor ; TNFR: Tumor necrosis factor receptor; NF-κB: Nuclear factor-kappa B; IκB: I kappa B; DNA: Deoxyribonucleic acid; IL-6: Interleukin-6; IL-6R: Interleukin-6 receptor; IL-4: Interleukin-4; IL-4R: Interleukin-4 receptor; IL-2: Interleukin-2; IL-2R: Interleukin-2 receptor; IL-1A: Interleukin-1a; STAT: Signal transducer and activator of transcription; MAF-C: Musculoaponeurotic fibrosarcoma oncogene; MYD88: The canonical adaptor for inflammatory signaling pathways downstream of members of the Toll-like receptor (TLR) and interleukin-1 (IL-1) receptor families; IRAK: IL-1R-associated kinase; TRAF6: TNF receptor associated factor 6; MAPK3: Mitogen-activated protein kinase 3; TRAF2: TNF receptor associated factor 2; MAP3K5: Mitogen-activated protein kinase kinase kinase 5; TIMP1: The tissue inhibitor of metalloproteinases 1; MMP9: Matrix metallopeptidase 9; pro-TGFβ: Pro-transforming growth factor-beta; TAK1: Transforming growth factor beta-activated kinase 1; JNK: C-Jun N-terminal kinase; NOS2: Nitric oxide synthase. Drawn by Figdraw.

Figure 4 Adenosine triphosphate causes the loss of mitochondrial membrane potential, the disruption of mitochondrial integrity, the production of reactive oxygen species and alterations in mitochondrial membrane permeability, collectively leading to cell deaths. ATP: Adenosine triphosphate; P2RX: Purinoceptor receptor P2X; PANX1: Pannexin 1; DNA: Deoxyribonucleic acid; ROS: Reactive oxygen species; mPTP: Mitochondrial permeability transition pore. Drawn by Figdraw.

AICD SIGNALING PATHWAY IN CARDIOMYOPATHY

Cardiomyopathy is a condition characterized by the dysfunctions of heart muscles, leading to impaired cardiac functions. One of the key signaling pathways implicated in the pathogenesis of cardiomyopathy is the AICD signaling pathway. ATP is a critical molecule involved in cellular energy metabolism and signaling. In the context of cardiomyopathy, the dysregulation of ATP signaling might trigger cell deaths and provoke the progression of the disease. Several researches have explored different aspects of this pathway, shedding light on the role of ATP and its receptors in promoting cell deaths in cardiomyocytes

Chronic diabetes leads to myocardial structural and functional defects, a hallmark of diabetic cardiomyopathy (DCM). Its features include myocardial fibrosis, microvascular diseases, myocardial cell apoptosis and energy metabolism disorders, ultimately leading to dysfunctions in cardiac diastolic and systolic functions. Mitochondrial dysfunctions are a hallmark of DCM, affecting various aspects of cardiomyocyte functions, by imparing oxidative stress, metabolic shift, signal cascade and cell deaths. Under typical conditions, mitophagy facilitates the lysosomal degradation of damaged mitochondria. Impaired mitophagy causes the buildup of dysfunctional mitochondria, leading to cardiomyocyte death[18]. Through the induction of cardiomyocyte deaths via norepinephrine, doxorubicin or H₂O₂, all these three stimuli significantly increase apoptosis and necrosis in alpha1-adrenergic receptor knockout (α1ABKO) cardiomyocytes. The reconstitution of the alpha1A (α1A) subtype, but not the alpha1B subtype, is able to rescue α1ABKO cardiomyocytes from cell deaths caused by each stimulus. The constitutive expression of active mitogen-activated protein kinase kinases 1 (MEK1) in α1ABKO cardiomyocytes rescues them from deaths induced by norepinephrine. In α1ABKO cardiomyocytes, only the α1A-adrenergic receptor activates extracellular-regulated kinase, and the expression of a dominant-negative MEK1 entirely inhibits the α1A survival signal. This demonstrates the protective role of α1-adrenergic receptors in these cells, which may be involved in the ATP-induced cardiomyocyte death signaling pathway[19].

Studies have found that apoptotic cell deaths play a crucial role in the development of DCM. Angiotensin II (Ang II) induces cardiac cell deaths by inducing reactive oxygen and nitrogen species in lab-based and organism-based studies. Treatment of H9c2 cells with varying concentrations of Ang II significantly triggers apoptosis, which is fully inhibited by the p53 inhibitor Pitithrin-α. This inhibitor also enhances p53 phosphorylation, DNA double-strand breaks, and the B cell lymphoma 2-associated X protein (Bax)/B cell lymphoma 2 (Bcl-2) ratio. Moreover, it has been discovered that the antioxidant metallothionein has preventive effect on Ang II-induced p53 activation and its apoptotic death signals[20]. In diabetic rats induced by streptozotocin and cardiomyocytes exposed to high glucose, microRNA (miR)-30d upregulation enhances cardiomyocyte pyroptosis. This study highlights the influence of miRs on cell death regulation in cardiomyopathy, potentially interacting with ATP-induced signaling pathways[21]. Chronic hyperglycemia impairs vascular functions by influencing vascular smooth muscle cells (VSMCs) and altering intracellular Ca²⁺ dynamics. Employing Fura-2-AM Ca²⁺ imaging to examine intracellular calcium signaling in VSMCs from diabetic fatty Zucker rats reveals that type 2 diabetes mellitus (T2DM) diminishes calcium release from the sarcoplasmic reticulum and enhances store-operated channel activity. At the initial stage of ATP-induced Ca²⁺ transients, key calcium extrusion mechanisms (sarco-endoplasmic reticulum Ca-ATPase, plasma membrane Ca²⁺-ATPase and plasma membrane Na⁺/Ca²⁺ exchanger) show enhanced activity. In the later stage, Zucker rats exhibit an initial rise in cytosolic calcium, followed by a more pronounced increase during the plateau phase, potentially driving vascular dysfunction associated with T2DM[22]. Therefore, some studies have also found that glucagon-like peptide-1 (GLP-1) safeguards cardiomyocytes against apoptosis caused by advanced oxidation protein products through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/bad signaling pathway, revealing the potential mechanism involved in GLP-1 in preventing cardiomyocyte deaths[23].

Hypertrophic cardiomyopathy (HCM) is a major driver of HF and sudden deaths in adolescents and young adults. Increased levels of yes-associated protein 1 (YAP) mRNA and proteins, and also decreased phosphorylation at serine 127 of YAP, have been observed in samples from patients with HCM and a mouse model of transverse aortic constriction, which are accompanied by increased YAP-mediated gene transcription in hypertrophic heart tissues. It has been discovered that mammalian sterile 20-like kinase 1 mediates the targeting of the Hippo/YAP pathway to the PI3K/Akt/forkhead box O3 (FoxO3) signaling pathway, regulating changes in HCM. This study provides insights into how the dysregulation of signaling pathways can contribute to the pathogenesis of cardiomyopathy, potentially involving AICD signaling pathways[24]. Mutations reduce the ratio of ATP/ADP and mitochondrial membrane potential, causing the increase in intracellular Ca²⁺ concentration, a hallmark of HCM-specific electrical disturbances[25]. The 31P magnetic resonance spectroscopy in rats demonstrate notable impairments in cardiac energy metabolism, indicated by a 31% reductionin in the phosphocreatine/ATP ratio (P < 0.05)[26]. The gene myosin-binding protein C 3 (MyBPC3), encoding for cardiac myosin-binding protein C, is a major genetic factor of HCM. This "heart-specific" MyBPC3 gene is transcribed and expressed in cardiac fibroblasts across species, as well as in NIH3T3 fibroblasts. The clustered regularly-interspaced short palindromic repeats-mediated knockout of MyBPC3 in NIH3T3 fibroblasts triggers the activation of the nuclear factor κB signaling pathway, leading to the upregulation of transforming growth factor-β1 (TGF-β1) and other pro-inflammatory genes. Elevated TGF-β1 levels upregulate hypoxia-inducible factor-1α and its glycolytic targets, including glucose transporter type 1, LDHA, and phosphofructokinase. This boosts aerobic glycolysis and ATP generation, driving cardiac fibroblast activation and advancing HCM progression[27].

Acute MI (AMI) can induce myocardial injuries or necrosis, which may lead to ischemic cardiomyopathy. A study examines how varying levels of PD1+ T cell expression in the peripheral blood of AMI patients impact cardiac function prognosis. It is found that the PD1/PD-L1 signaling pathway inhibits T cell activity, leading to cell deaths and thereby affecting cardiac functions[28].

Chemotherapy is an important means of treating tumors, and studies have found that chemotherapy drugs have certain cardiotoxic effects. The study is focused on the cardiotoxic effects of chemotherapies, including anthracyclines and trastuzumab, on patients with breast cancer. Researchers employed contrast-enhanced cardiovascular magnetic resonance imaging to evaluate the impact of these treatments on heart functions[29]. Another study’s researchers conduct a phase II trial of RAD001 for management of refractory, recurrent, locally-advanced head and neck squamous cell carcinoma, aiming to explore the correlations between the activity of the treatment regimens and markers of the epidermal growth factor receptor/mammalian target of the rapamycin pathway. This pathway is recognized as essential for cell survival and proliferation, whose dysregulation can lead to aberrant cell death signaling[30]. Furthermore, researchers have investigated the Hedgehog signaling pathway inhibitor PF-04449913 inpatients with acute myeloid leukemia at high risk, aiming to determine whether targeting this pathway can decrease disease relapse after stem cell transplantation. The Hedgehog pathway is involved in various cellular processes, including cell survival and proliferation, and its dysregulation has been implicated in cancer progression. Understanding the effects of targeting this pathway in leukemia may provide insights into similar pathways involved in cardiomyopathy[31]. For a comprehensive overview of in vitro and in vivo models exploring AICD's role in cardiomyopathy, refer to Table 1[32-41].

Table 1 Experimental studies examining the role of adenosine triphosphate-induced cell death in cardiomyopathy.

Ref.	Year	Model	Marker(s)	Compound/target	Effect(s)
Wu et al[41]	2024	LPS-induced SIC model	LVEF, LVFS, SV, BNP and IL-1β and IL-18	IP3R2	The up-regulation of NLRP3 Leads to GSDMD-induced myocardial tissue pyroptosis
Croteau et al[40]	2023	The high fat-sucrose diet-induced diabetic cardiomyopathy mice model	PCr/ATP	Ertugliflozin	Decreases elevated intracellular sodium
Belosludtseva et al[39]	2023	ISO-induced myocardial injuries	TnI, the ratio of AST/ALT, level of LV myocardial ATP	Uridine	Inhibit ISO-induced excessive production of ROS and lipid peroxidation in rat heart mitochondria
Zhang et al[38]	2016	Cardiotoxicity of ADR	PGC-1α, NRF-1 and TFAM	Cryptotanshinone	Increase the activity of complexes other than Complex II, significantly promoting the production of ATP energy
Ding et al[37]	2023	Doxorubicin-induced cardiomyopathy	Enzymes CK, CK-MB and LDH	SGI	Increase ATP levels and mitochondrial membrane potential and inhibit intracellular ROS
Panxia et al[36]	2019	Doxorubicin-induced cardiomyopathy	SESN2	SESN2	Improve mitochondrial function and mitochondrial autophagy to prevent Dox-induced cardiotoxicity
Song et al[35]	2021	DCM	caspase 1	SIRT3	Promote myocardial necrotic apoptosis in DCM mice
Wang et al[34]	2025	CLP-SIC mice model	SOD and GSH-Px	PGJXD	Inhibit inflammatory responses and improve cardiomyocyte apoptosis, alleviate mitochondrial structural abnormalities in CLP model, reduce oxidative stress damage and promote energy synthesis
Guo et al[32]	2025	STZ/HFD-induced mouse model	TNF-α, IL-6, Masson Trichrome staining, ORO staining	SIRT2	SIRT2-mediated deacetylation at K239 enhances CPT2 ubiquitination
Yuan et al[33]	2025	CLP mouse model	LDH	5'tiRNA-33-CysACA-1	The key molecule PGC-1α promotes the development of SCM by targeting mitochondrial biogenesis

LPS: Lipopolysaccharide; SIC: Silicon carbide; LVEF: Left ventricular ejection fraction; BNP: B-Type Natriuretic Peptide; SV: Stroke volume; IP3R2: Inositol 1,4,5-triphosphate receptor, type 2; LVFS: Left ventricular fractional shortening; IL-1β: Interleukin-1 beta; IL-18: Interleukin-18; GSDMD: Gasdermin; ATP: Adenosine triphosphate; PCr: Creatine phosphate; ISO: Isoproterenol; TnI: Troponin I; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ROS: Reactive oxygen species; ADR: Adverse drug reaction; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1 alpha; NRF-1: Nuclear respiratory factor 1; TFAM: Mitochondrial transcription factor A; CK: Creatine kinase; CK-MB: Creatine kinase MB; LDH: Lactate dehydrogenase; DCM: Diabetic cardiomyopathy; SESN2: Sestrin2; SIRT3: Sirtuin 3; CLP: The cecal ligation and puncture; SOD: Superoxide dismutase; GSH-Px: Glutathione peroxidase; PGJXD: Po-Ge-Jiu-Xin decoction; SIRT2: Sirtuin 2; STZ/HFD: High-fat diet and streptozotocin; TNF-α: Tumour necrosis factor alpha; IL-6: Interleukin-6; ORO: Oil Red O; SCM: Septic cardiomyopathy.

In conclusion, literatures on AICD signaling pathways in cardiomyopathy highlight the intricate network of molecular mechanisms that contribute to cardiac dysfunctions and disease progression. By understanding these pathways, researchers can develop targeted therapies to prevent cell deaths and improve the outcomes of patients with cardiomyopathy. The modulation of potassium channels[42], antioxidant therapies[43] and targeting immunogenic cell death pathways[44] are promising approaches to prevent AICDs and improve the outcomes of patients with cardiomyopathy.

AICD IN MYOCARDIAL IRI

Myocardial IRI is a significant cause of cell deaths and organ damage in various pathologies, including MI, stroke and acute kidney injuries. IRI is a significant concern of patients undergoing high-risk coronary artery bypass graft surgeries. Several Numerous studies have investigated various mechanisms and therapeutic targets to alleviate the harmful impact of IRI on the heart. Myocardial IRI involves complex and various mechanisms, such as ROS generation, altered cellular osmotic balance, and inflammatory activation. Elevated Ca²⁺, altered oxygen levels, and mitochondrial ROS (mROS) production cumulatively induce permanent activation of mitochondrial permeability transition pores. The generation of ROS and subsequent oxidative stress serve as pivotal drivers of cellular injury and functional disturbance. These pathways are closely tied to NLRP3 inflammasome activation, which drives cell death via caspase-1 pathway enhancement and interleukin(IL)-18 production[45].

Studies using mice with heterozygous sirtuin 6 (SIRT6) knockout [SIRT6 (+/-)] and in vitro cardiac myocyte models have found that the partial loss of SIRT6 exacerbates myocardial injuries, ventricular adaptation and oxidative stress. SIRT6 increases the adenosine monophosphate (AMP)/ATP ratio, and activates the AMP-activated protein kinase (AMPK)-FoxO3α axis, which boosts the level of antioxidant genes like manganese superoxide dismutase and catalase. It enhances antioxidant defenses and reduces oxidative stress, thereby safeguarding the cardiac system against IRI[46].

The reversal of Ca²⁺ influx in cardiomyocytes leads to reduced mechanical function, ultrastructural damage, ATP depletion, elevated intracellular calcium, and the onset of apoptosis. The 'calcium paradox' signifies the substantial anatomical and physiological alterations in the myocardium that occur when the heart undergoes a short calcium-free interval followed by calcium reintroduction. A heart undergoing calcium paradox is a standard model for studying cellular injury mechanisms due to intracellular calcium overload in cardiac muscle cells during reoxygenation following hypoxia or ischemia. A study has found that after 30 minutes of myocardial ischemia, apoptotic cell deaths are exhibited after 60 minutes of reperfusion[47].

I/R-induced myocardial injuries are associated with mitochondrial-dependent apoptosis. The administration of demethylcoclaurine (intravenous injection) 1 hour prior to IRI significantly reduces the release of CYTC, caspase-3 activity and Bax expression, while upregulating Bcl-2, heme oxygenase-1 (HO-1) and HO enzyme activity expression in the left ventricle. It has been found that HO-1 is a cornerstone of in the protective effect of demethylcoclaurine against myocardial IRI[48].

Mitochondria have been identified as key players in cardiac microvascular IRI[49]. Inhibiting mitochondrial fission protein dynamin-related protein 1 can alter the mitochondrial metabolic capacity to alleviate IRI[50]. Tumor-necrosis-factor-receptor-associated protein 1 has been identified as a protective factor against myocardial IRI by ameliorating mitochondrial dysfunctions[51]. Irisin has been shown to attenuate myocardial IRI and ameliorate mitochondrial functions through the AMPK pathway in diabetic mice[52].

Moreover, the role of oxidative stress and inflammation in exacerbating IRI has been a focus of research. PICOT[53], FoxO4[54], caspase 1[55] and interferon regulatory factor 9[51] have been identified as factors that alleviate myocardial IRI by reducing the intracellular levels of ROS. It has been implicated in promoting myocardial IRI through oxidative-stress-induced apoptosis. The use of PNaktide to inhibit the Na/K-ATPase/Src/ROS amplification signaling pathway can alleviate myocardial IRI[56]. The hereditary deficiencies of glutathione S-transferase P are associated with increased sensitivity of the myocardium to IRI[57]. The intravenous administration of lycopene has been shown to defend against myocardial IRI in a mouse model[58]. Supplementing antioxidants such as ascorbic acid (vitamin C) can prevent oxidative stress and cell damage induced by I/R, reducing inflammation-induced myocardial injuries[59]. Those results emphasize the importance of antioxidant defense mechanisms in protecting the heart from IRI.

Exosomal miRs have the potential to manage therapeutics for IRI[60]. MiR-21 may protect against cardiocyte apoptosis induced by I/R and hypoxia-reperfusion through the phosphatase and tensin homolog/Akt-dependent mechanism[61]. Exosomal miR-455-3p from bone-marrow-derived mesenchymal stem cells has been shown to prevent cardiac IRI[60]. For a full list of the roles of AICD in IRI, see Table 2[62-71]. Meanwhile, enhancing the mitochondrial pyruvate metabolism has been proposed as a potential strategy to ameliorate myocardial IRI. By redirecting pyruvate towards oxidation, it may be possible to reduce cardiomyocyte damage and improve cardiac functions during reperfusion[72]. Additionally, oxidative stress's involvement in IRI and the potential therapeutic benefits of traditional Chinese medicines have been investigated as alternative treatment strategies[73]. In conclusion, targeting oxidative stress, mitochondrial dysfunctions and apoptosis may offer new treatment strategies for managing the relationship with IRI and AICD in cardiovascular diseases.

Table 2 Experimental studies examining the role of adenosine triphosphate-induced cell death in ischemia-reperfusion injury.

Ref.	Year	Model	Marker(s)	Compound/target	Effect(s)
Zhang et al[70]	2024	Temporary ligation of the LAD for 40 minutes to induce myocardial I/R injury	cTnT, LVEF, LVFS, LVEDD and LVESD	B. infantis or its metabolite inosine	Activate A2AR
Chen et al[69]	2024	A thoracotomy was performed, and reversible sutures were placed around the LAD. By tightening the sutures for 30 minutes and then loosening them, myocardial I/R was induced	NIR imaging	IR-780	Binds to the F0F1-ATP synthase of cardiomyocytes, inducing mitochondria to enter a "resting state"
Chen et al[68]	2022	Mice undergo 60 minutes of ischemia in the LAD by ligating the artery, followed by 120 minutes of reperfusion after releasing the ligation to establish an IRI model	IL-6, IL-10, TNF-α, MIF, P-AMPK α, GLUT4 and Bcl-2	Dexmedetomidine	α2-AR stimulant
Rusiecka et al[67]	2023	Perform a left thoracotomy to access the heart, suture around the LAD with 8-0 Prolene suture, and form a loop using a small piece of polyethylene tubing. Induce ischemia by pulling the loop and maintain the occlusion for 30 minutes. Reperfuse after releasing the clamp for 24 hours	cTnI	Panx1	Increased mitochondrial ATP content
Flori et al[66]	2023	Acute myocardial injury and I/R injury caused by coronary artery occlusion	cTnI	ERU, mitoKATP channel	Activate mitoK channels, mitoKv7.4, and mitoKATP channels
Wu et al[65]	2022	Ligate the LAD to construct an in vivo I/R model	Infarct size, LDH levels, and serum cTnT levels	IF1	Block the reversal of F1Fo-ATP synthase; Activate AMPK
Wang et al[64]	2023	Exposure of the heart is achieved through a left thoracotomy, and AMI is induced by ligating the LAD at its temporal aspect for 30 minutes, followed by releasing the ligation to cause reperfusion injury after 30 minutes	LDH and CK-MB	AASP	Increase mitochondrial membrane potential, restore ATP synthase activity
Huang et al[63]	2024	Induce myocardial ischemia through methods such as coronary artery ligation, and then restore blood flow after a certain period to simulate the reperfusion process	LDH, CK, Acetylation level of SF3A2	Ginsenoside Rb2	Inhibit p300-mediated acetylation at lysine 10 of SF3A2 to promote selective splicing of the Fscn1 gene, thereby enhancing Fscn1 expression
Cai et al[62]	2023	LAD ligation mouse model	LDH, ACSL4, TfR, SLC7A11, GPX4 and 4- HNE	Alox15/15-HpETE	Promote the binding of Pgc1α with ubiquitin ligase ring finger protein 34
Chen et al[71]	2024	An open-chest surgery was performed to expose the heart, and then the LAD was sutured with 9-0 suture thread	cTnI and CK-MB	GAS	GAS improved mitochondrial autophagy by PINK1/Parkin

LAD: Left anterior descending coronary artery; cTnT: Cardiac troponins T; cTnI: Cardiac troponins I; LVEF: Left ventricular ejection fraction; LVFS: Left ventricular fractional shortening; LVEDD: Left ventricular end-diastolic diameter; LVESd: Left ventricular end-systolic diameter; B. infantis: Bifidobacterium infantis; A2AR: Adenosine A2A receptors; NIR: Near-infrared; IRI: Ischemia/reperfusion injury; IL-6: Interleukin-6; IL-10: Interleukin-10; TNF-α: Tumour necrosis factor alpha; MIF: Macrophage migration inhibitory factor; P-AMPK α: Phosphorylated AMP-activated protein kinase α; GLUT4: Glucose transporters type 4; Bcl-2: B cell lymphoma 2; α2-AR: Α2-adrenergic receptor; ERU: Erucin; mitoKATP: Mitochondrial ATP-sensitive potassium channel; IF1: F1Fo-ATPase inhibitor 1; AMI: Acute myocardial ischemia; TfR: Transferrin receptor; SLC7A11: Solute carrier family 7a member 11; GPX4: Glutathione peroxidase 4; 4-HNE: 4-hydroxy-2-nonenal; Pgc1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; GAS: Gastrodin; PINK1: PTEN-induced kinase 1.

HF WITH PRESERVED EJECTION FRACTION AND AICDS

HF with preserved ejection fraction (HFpEF) is an intricate clinical syndrome characterized by diastolic dysfunctions and preserved LVEF. The pathophysiology of HFpEF involves various factors such as microvascular dysfunctions, abnormal metabolic substrate shifts and myocardial fibrosis. The involvement of programmed cell death types in the development of such HF is becoming increasingly certain. Studies have shown that metabolic abnormalities and microvascular dysfunctions may precede the onset of diastolic dysfunctions in patients with HFpEF[74], which underscores the need to understand HFpEF's underlying mechanisms for developing effective treatments. AICD and HF are complex processes that involve various mechanisms and pathways within the cardiovascular system. Apoptosis, or programmed cell deaths, is critical to the mechanisms underlying HF. Research indicates that apoptosis in myocytes, endothelial cells and fibroblasts precede ventricular decompensation and correlate with the deterioration of cardiac functions of models with dilated cardiomyopathy induced by ventricular pacing[75].

Moorjani et al[76] directly demonstrated the function of apoptosis in the development of HF. They studied the expression of apoptotic genes in the left ventricular tissues of patients at different stages of the process, whose HF was caused by volume overload. In the group of patients with preserved left ventricular functions, the expression of pro-apoptotic factors, including Bax, p53, TNFR1, and caspases 3, 8, and 9, was significantly lower, increasing as HF progressed. This highlights the influence of volume overload on the enhancement of apoptosis through both intrinsic and extrinsic pathways in HF. Elevated levels of the anti-apoptotic protein Bcl-xL are linked to declining left ventricular functions, indicating an activated compensatory mechanism to prevent apoptosis.

TRAIL receptors are embedded in cell membranes. TRAIL-receptors 1 and 2 are death receptors that trigger apoptosis via the extrinsic apoptotic pathway. TRAIL-receptor 2 levels are significantly elevated in HFpEF patients compared to fit individuals. TRAIL-receptor 2 is also significantly increased in obese patients with HFpEF compared to non-obese ones[77]. These results indicate that the activity of TRAIL pathway influences the pathogenesis of HFpEF. Elevated TRAIL levels in HFpEF patients correlate with improved prognosis[78].

In a failing heart, oxidative stress has been identified as a major determinant of ventricular dysfunctions and failure. Oxidative-stress-mediated cardiac cell deaths, particularly through the depletion of nucleotide nicotinamide adenine dinucleotide levels and the reduced silent information regulator 2 deacetylase activity, have been implicated in the pathogenesis of HF[79]. Furthermore, rhein blocks P2X7R in rat peritoneal macrophages, hindering ATP/2',3'-[benzoyl-4-benzoyl]-ATP-induced Ca²⁺ influx, membrane pore assembly and ROS generation, while also decreasing, IL-1β release, phagocytosis and cell deaths[80]. Clinical trials show that IL-1β and IL-18 inhibitors markedly reduce the occurrence of major adverse cardiac events, including MI and HF[81]. P2X7 is unique among P2X receptors, functioning both as a conventional receptor activated by molecules and as a channel permitting substance passage, which can result in cell death after extended ATP exposure[82]. Meanwhile, the overexpression of P2X6 receptors in patients subjected to heart transplantation has been associated with myocardial cell deaths[83].

Besides apoptosis, other forms of regulated cell deaths, such as necrosis and autophagy, have been implicated in the development of HF. Calcium- and mitochondrial-dependent cardiomyocyte necroses have been identified as primary mediators of HF, highlighting the importance of mitochondrial functions in cardiac cell deaths[84].

In an adriamycin-induced rat HF model, the use of 3-methyladenine (3MA) reveals that 3MA significantly improves cardiac functions and alleviates mitochondrial damage; adriamycin induces the formation of autophagic vacuoles, whereas 3MA strongly downregulates the expression of Beclin 1 in adriamycin-induced hearts with HF and inhibits the formation of autophagic vacuoles. Autophagic cardiomyocyte deaths play a significant driver in the pathogenesis of rat-adriamycin-induced HF[85]. Moreover, inflammasomes, multi-proteins assembly responsible for initiating inflammation, have been implicated in adverse cardiac remodeling following AMI. The modulation of inflammasomes may represent a unique therapeutic strategy to limit cell deaths and prevent HF after MI[86]. Targeting the dysregulated interplay between calcium signaling and ROS in mitochondria may ameliorate the progression of HF by modulating redox signaling pathways[87].

The mild uncoupling of mitochondria provides protective effect against HF. Studies have shown that typical chemicals such as carbonyl cyanide-p-trifluorometh oxyphenyl hydrazone, nicotinamide and BAM15 cause biphasic changes in signal transducers and activators of transcription 3 (STAT3) in cardiomyocytes, which activating it at low concentrations and inhibiting it at high concentrations, regardless of varying dose ranges. The low doses of these agents increase mROS generation marginally and later activate JAK/STAT3 in cardiomyocytes. Contrarily, elevated dosing regimens of these agents result in STAT3 inhibition, decreased ATP synthesis, and cardiomyocyte death. Dysregulated mROS generation from over-uncoupling inhibits STAT3 and diminishes ATP-induced AMPK activation. Low concentrations of these agents mitigate the inhibitor of doxorubicin-induced STAT3 and cardiomyocyte death, with STAT3 activation being essential for their cardioprotective effects. These agents, by mildly uncoupling mitochondria in cardiomyocytes, are typified by STAT3 activation and increased ATP levels. Conversely, over-uncoupling results in STAT3 inhibition, decreased ATP levels and cellular damage[88]. For a full list of the roles of AICD in HFpEF and HF (Table 3)[89-98].

Table 3 Experimental studies examining the roles of adenosine triphosphate-induced cell death in heart failure with preserved ejection fraction and heart failure.

Ref.	Year	Model	Marker(s)	Compound/target	Effect(s)
Schiattarella et al[98]	2021	The model combines metabolic alterations (exposure to HFD) and endothelial dysfunction-driven hypertension (modeled using a NOS inhibitor, L-NAME) to simulate clinical HFpEF	FoxO1, STUB1	Xbp1s-FoxO1	Activate E3 ubiquitin ligase STUB1
Yan et al[97]	2024	TAC-induced chronic HF and doxorubicin-induced acute HF mouse models	Mitochondrial OCR Analysis, LDH Activity and CK-MB	DDX17	Promoting mitochondrial homeostasis through the BCL6-DRP1 pathway
Zhang et al[96]	2023	Injection of DOCA, Ang II, and WD for 18 weeks to establish HFpEF pigs	Th, IL-6 and TNF-α	Dapagliflozin	Elevate β-hydroxybutyrate-activated citrate synthase activity
Zhang et al[95]	2024	Continuous infusion of AngII induces cardiac remodeling	LAMP1, LC3II, p62, IL-6, MCP-1, IL-1β	Schaftoside	Inhibit CaMKII-δ activity
Shou et al[94]	2022	Establishing a hypertension-induced HFpEF model in Dahl/SS rats with high-salt feeding	Mfn2 and Drp1	PINK1	Phosphorylation of Drp1S616 to improve mitochondrial fission and alleviate mitochondrial dysfunction
He et al[93]	2022	High-salt diet induces HFpEF	LVEF and E/A ratio, Masson's trichrome staining, WGA staining	Canagliflozin	Upregulate p-AMPK and SIRT1, and significantly induce the expression of PGC-1α
Shao et al[92]	2024	Ligation of the LAD induced	RXRa, Ndufs4	AS-III	Activate RXRa dimer
Zhang et al[91]	2024	DOX-induced HF	IL-1β, IL-18, TNF-α, TLR2	Circ-0006332	Downregulate miR-143 and upregulate TLR2 to stimulate cardiomyocyte pyroptosis
Lyu et al[90]	2023	Ligation of LAD induces HF	ATP, AMP, ADP	Empagliflozin	Downregulate the expression of mitochondrial fission proteins and upregulate the expression of mitochondrial fusion proteins in HF mice
Yang et al[89]	2022	DOX-induced HF	BNP, ATP1α1	Trimetazidine	Inhibit KAT

HFD: High-fat diet; FoxO1: Forkhead box O 1; STUB1: STIP1 homology and U-box-containing protein 1; NOS: Nitric oxide synthase; L-NAME: Nω-nitro-L-arginine methyl ester; TAC: Transverse aortic constriction; OCR: Oxygen consumption rate; DDX17: DDEAD-box helicase 17; CaMKII-δ: Ca²⁺/calmodulin-dependent kinase II-δ; BCL6-DRP1: B-cell lymphoma 6 - dynamin-related protein 1; DOCA: Deoxycorticosterone acetate; WD: Western diet; Th: Tyrosine Hydroxylase; LAMP1: Lysosome associated membrane proteins 1; LC3II: Light chain 3 II; MCP-1: Monocyte chemoattractant protein-1; Mfn2: Mitofusin 2 protein; Drp1: Dynamin-related protein 1; PINK1: PTEN-induced kinase 1; WGA: Wheat germ agglutinin; RXRa: Retinoid X receptor protein a; Ndufs4: Ubiquinone oxidoreductase subunit S4; AS-III: Arsenic-III ;DOX: Doxorubicin; TLR2: Toll-like receptor-2; Circ-0006332; ATP1α1: Na²⁺/ K⁺ATPase subunit alpha 1; KAT: 3-ketoacyl-CoA thiolase.

Overall, understanding the fundamental mechanisms of regulated cell deaths, including apoptosis, necrosis and autophagy, is crucial for unraveling the complex pathophysiology of HF. Further research into the roles of immunogenic cell deaths, ferroptosis and other forms of regulated cell deaths in cardiac diseases is needed to develop cutting-edge therapeutic strategies for the prevention and management of HF[99]. Mitochondrial-ATP-sensitive potassium channels have been shown to play a protective role in ischemic preconditioning, reducing reperfusion arrhythmias and preventing cell deaths[100]. Interventions such as diet-induced weight loss and exercise training have been shown to improve the outcomes of patients with HFpEF[101], which may help to improve mitochondrial functions and metabolic pathways, leading to better outcomes of patients with HFpEF. By targeting specific pathways involved in AICD, such as oxidative stress, mitochondrial dysfunctions and inflammatory responses, researchers may be able to develop more effective interventions to mitigate the progression of HF and improve patient outcomes.

NON-MYOCARDIAL AICD

Non-myocardial AICD are a complex phenomenon, currently lacking extensive research. Some existing studies provide insights into the mechanisms of cell deaths in different contexts, including myocardial ischemia and reperfusion injuries. ATP is a critical molecule in cellular energy metabolism and plays a crucial role in cell survival. However, under certain conditions, ATP can also induce deaths of non-myocardial cells, such as cardiac fibroblasts. One study investigates the molecular basis of AICDs in breast cancer cells and identifies an ATP-activated non-selective cation channel[15]. Similarly, another study of Wang et al[14] demonstrates that in the context of myocardial reperfusion injuries, Ca²⁺-mediated cell deaths have been implicated as a mechanism of cell damage. ATP-induced cardioprotection against myocardial ischemia is associated with a reduction in cardiomyocyte apoptosis. De-energization resulting from hypercontracture-mediated cell deaths is a consequence rather than a cause of cell deaths during reperfusion. Mechanisms unrelated to mitochondrial permeability transition (MPT) are also important, which are present in not only cardiac muscle cells but also other types of cells. Altered Ca²⁺ handling includes increased cytosolic Ca²⁺ levels, leading to the oscillatory activation driven by proteasome-mediated proteolysis and sarcoplasmic reticulum, which can cause over contraction, but may also lead to MPT due to preferential Ca²⁺ transfer between the sarcoplasmic reticulum and mitochondria through cytosolic Ca²⁺ microdomains[102]. Conversely, permeability transition can exacerbate altered Ca²⁺ handling and promote over contraction. This suggests that ATP synthesis and energy metabolism play a crucial role in determining cell fate during myocardial reperfusion[103]. In the context of sepsis-induced myocardial dysfunctions, levosimendan has been proposed as a potential medication for patients presenting with myocardial dysfunctions. Definitive studies supporting levosimendan as the optimal choice of medication are lacking. Further research is needed to determine the efficacy of levosimendan in preventing cell deaths in sepsis-induced myocardial dysfunctions[104]. Additionally, this study shows that mesenchymal-stem-cell-derived exosomes can increase ATP levels in myocardial cells, suggesting a potential therapeutic strategy for reducing cell deaths in the context of MI[104].

Overall, literatures on non-myocardial AICDs highlight the complex interplay among ATP metabolism, cell survival and cell death processes. Further research is needed to elucidate the specific mechanisms underlying AICDs in different cell types and pathological conditions. Understanding these mechanisms could pave the way for innovative treatments aimed at reducing cell death and enhancing outcomes in conditions like myocardial IRI.

CONCLUSION

In essence, AICD is a key contributor to the development of HF, affecting myocardial diseases, IRI and HFpEF through aspects of mitochondrial energy metabolism, redox balance and calcium homeostasis. Understanding the link between AICD and HF may uncover novel therapeutic targets for HF treatment. Future research should aim to overcome the limitations of these pathways, enhance our understanding, and develop targeted interventions to prevent and improve outcomes for HF patients. Further research on low molecular weight compounds, biopharmaceuticals, and gene-based therapies aimed at AICD pathways may pave the way for innovative cardiovascular disease therapies. Well-designed clinical trials are crucial for evaluating the safety and efficacy of novel AICD-targeted therapies, bridging the gap between basic research and clinical application.