Potential Roles of IP3 Receptors and Calcium in Programmed Cell Death and Implications in Cardiovascular Diseases

Inositol 1,4,5-trisphosphate receptors (IP3Rs) play a crucial role in maintaining intracellular/cytosolic calcium ion (Ca2+i) homeostasis. The release of Ca2+ from IP3Rs 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 IP3Rs is linked to the pathogenesis of various cardiac conditions. The overactivation of IP3Rs results in the dysregulation of Ca2+ concentration ([Ca2+]) within cytosolic, mitochondrial, and nucleoplasmic cellular compartments. In cardiovascular pathologies, two isoforms of IP3Rs, i.e., IP3R1 and IP3R2, have been identified. Notably, IP3R1 plays a pivotal role in cardiac ischemia and diabetes-induced arrhythmias, while IP3R2 is implicated in sepsis-induced cardiomyopathy and cardiac hypertrophy. Furthermore, IP3Rs 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 IP3R antagonists have emerged as promising strategies against IP3R-related pathologies suggesting their potential therapeutic potency. This review summarizes the roles of IP3Rs 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.