Targeting the Ca2+ signaling toolkit as an alternative strategy to mitigate SARS-CoV-2-induced cardiovascular adverse events.

Abstract

Ca²⁺ signaling events are essential for maintaining cardiovascular health, regulating critical functions in both endothelial and cardiac cells. SARS-CoV-2 infection impinges this delicate balance, leading to severe cardiovascular complications. SARS-CoV-2 binds to the ACE2 receptor on endothelial and cardiomyocyte surfaces, triggering abnormal increases in intracellular Ca²⁺ levels that promote endothelial dysfunction, inflammation, and hypercoagulation. In endothelial cells, this dysregulation activates a pro-inflammatory state and compromises vascular integrity. In cardiomyocytes, SARS-CoV-2-induced Ca²⁺ imbalances contribute to arrhythmias and heart failure by promoting abnormal Ca²⁺ cycling and energy metabolism disruptions. Additionally, the cytokine storm associated with COVID-19 amplifies these effects by further altering Ca²⁺ handling, enhancing inflammatory responses, and promoting thrombosis. Targeting Ca²⁺ channels, particularly endolysosomal two-pore channels, represents a promising therapeutic approach to counteract SARS-CoV-2's effects on Ca²⁺ dynamics. Several FDA-approved drugs that modulate Ca²⁺ signaling could be repurposed to prevent viral entry and mitigate cardiovascular damage. Understanding these Ca²⁺-related mechanisms offers valuable insights for developing treatments to reduce cardiovascular risk in COVID-19 and potentially future viral infections impacting the cardiovascular system.