Targeting Calcium Homeostasis in Myocardial Ischemia/Reperfusion Injury: An Overview of Regulatory Mechanisms and Therapeutic Reagents

Abstract

Calcium homeostasis plays an essential role in maintaining excitation-contraction coupling (ECC) in cardiomyocytes, including calcium release, recapture, and storage. Disruption of calcium homeostasis may affect heart function, leading to the development of various heart diseases. Myocardial ischemia/reperfusion (MI/R) injury may occur after revascularization, which is a treatment used in coronary heart disease. MI/R injury is a complex pathological process, and the main cause of increased mortality and disability after treatment of coronary heart disease. However, current methods and drugs for treating MI/R injury are very scarce, not ideal, and have limitations. Studies have shown that MI/R injury can cause calcium overload that can further aggravate MI/R injury. Therefore, we reviewed the effects of critical calcium pathway regulators on MI/R injury and drew an intuitive diagram of the calcium homeostasis pathway. We also summarized and analyzed calcium pathway-related or MI/R drugs under research or marketing by searching Therapeutic Target and PubMed Databases. The data analysis showed that six drugs and corresponding targets are used to treat MI/R injury and involved in calcium signaling pathways. We emphasize the relevance of further detailed investigation of MI/R injury and calcium homeostasis and the therapeutic role of calcium homeostasis in MI/R injury, which bridges basic research and clinical applications of MI/R injury.

Keywords: Therapeutic Target Database; calcium homeostasis; calcium signaling pathway; myocardial ischemia/reperfusion injury; therapeutic reagents.

Figure 1

Venn diagram of drugs from MI/R injury and calcium signaling pathway. We collected 16 drugs for the treatment of MIR injury and 30 drugs involved in calcium signaling pathway. The MI/R drugs related to calcium signaling pathway include: adenosine, ridogrel, vorapaxar, metoprolol, flunarizine, and zoniporide hydrochloride.

Figure 2

Calcium overload is the important target of treating myocardial ischemia/reperfusion (MI/R) injury. The maintenance of calcium homeostasis requires the participation of multiple regulatory proteins including LTCC, RyR2, SERCA, NCX, PLB, FKBP12.6, and CaMK II. When MI/R occurs, calcium homeostasis will be broken and further developed into calcium overload. Calcium overload further exacerbates MI/R injury. Therefore, inhibiting calcium overload is an effective way to reduce MI/R injury. These drugs currently on the market or under investigation including adenosine, ridogrel, vorapaxar, metoprolol, flunarizine, and zoniporide hydrochloride, are for the treatment of MI/R injury or have the potential to treat MI/R injury. These drugs can play a cardioprotective role by regulating the calcium signaling pathway.