Inhibition of transient receptor potential vanilloid 4: A promising novel strategy for myocardial ischemia/reperfusion injury treatment

Myocardial ischemia-reperfusion (IR) injury remains a major clinical challenge, often exacerbating cardiac damage despite timely reperfusion. The transient receptor potential vanilloid 4 (TRPV4), a Ca²⁺-permeable non-selective cation channel, has emerged as a key mediator of IR injury. TRPV4 is widely expressed in cardiomyocytes, endothelial cells, and immune cells, and its activation under ischemic stress promotes Ca²⁺ overload, oxidative stress, inflammation, and endothelial dysfunction. Upregulation and membrane translocation of TRPV4 during IR aggravates intracellular Ca²⁺ influx, sarcoplasmic reticulum Ca²⁺ leak, and mitochondrial impairment. TRPV4 also amplifies reactive oxygen species (ROS) production, impairs antioxidant defenses, and triggers inflammatory signaling. Additionally, TRPV4 contributes to cardiomyocyte apoptosis, pyroptosis, and possibly ferroptosis. Preclinical studies demonstrate that selective TRPV4 antagonists (e.g., HC-067047, GSK2193874) significantly reduce infarct size, preserve cardiac function, suppress arrhythmias, alleviate myocardial stunning, and prevent coronary no-reflow. The age-related upregulation of TRPV4 further highlights its therapeutic relevance in elderly patients. Targeting TRPV4 thus represents a promising strategy to mitigate multifactorial myocardial injury and improve outcomes following reperfusion therapy.