Potential Roles of IP Receptors and Calcium in Programmed Cell Death and Implications in Cardiovascular Diseases.

Inositol 1,4,5-trisphosphate receptors (IPRs) play a crucial role in maintaining intracellular/cytosolic calcium ion (Ca) homeostasis. The release of Ca from IPRs serves as a second messenger and a modulatory factor influencing various intracellular and interorganelle communications during both physiological and pathological processes. Accumulating evidence from in vitro, in vivo, and clinical studies supports the notion that the overactivation of IPRs is linked to the pathogenesis of various cardiac conditions. The overactivation of IPRs results in the dysregulation of Ca concentration ([Ca]) within cytosolic, mitochondrial, and nucleoplasmic cellular compartments. In cardiovascular pathologies, two isoforms of IPRs, i.e., IPR1 and IPR2, have been identified. Notably, IPR1 plays a pivotal role in cardiac ischemia and diabetes-induced arrhythmias, while IPR2 is implicated in sepsis-induced cardiomyopathy and cardiac hypertrophy. Furthermore, IPRs have been reported to be involved in various programmed cell death (PCD) pathways, such as apoptosis, pyroptosis, and ferroptosis underscoring their multifaceted roles in cardiac pathophysiology. Based on these findings, it is evident that exploring potential therapeutic avenues becomes crucial. Both genetic ablation and pharmacological intervention using IPR antagonists have emerged as promising strategies against IPR-related pathologies suggesting their potential therapeutic potency. This review summarizes the roles of IPRs in cardiac physiology and pathology and establishes a foundational understanding with a particular focus on their involvement in the various PCD pathways within the context of cardiovascular diseases.