# BAK and BAX: Therapeutic Targets for Acute Myocardial Infarction and Myocardial Ischemia-Reperfusion Injury

## TL;DR

This paper reviews how BAK and BAX proteins contribute to heart cell death during heart attacks and reperfusion injury, and how targeting them could lead to new heart-protecting therapies.

## Contribution

The paper highlights the therapeutic potential of inhibiting BAK and BAX to reduce myocardial cell death and improve outcomes in heart attack patients.

## Key findings

- BAK and BAX are central to apoptosis and necroptosis in myocardial ischemia-reperfusion injury.
- Genetic removal of BAK and BAX in mice reduces infarct size and cell death in heart attack models.
- Inhibiting BAK and BAX shows promise as a strategy for cardiac protection in acute myocardial infarction.

## Abstract

A heart attack occurs when blood flow to the heart is blocked, causing the death of precious heart muscle cells. This not only damages the heart during the attack itself but can continue even after blood flow is restored, a phenomenon known as reperfusion injury. A major reason for this ongoing damage is the self-destruction of heart cells through processes called apoptosis and necroptosis. Our review focuses on two key proteins inside these cells, BAK and BAX, which act as central switches to initiate such cell death. We explain how various signals during a heart attack converge to activate BAK and BAX, leading to irreversible damage. Importantly, studies show that genetically removing BAK and BAX can significantly protect heart cells and reduce injury in animal models. We also summarize the exciting progress in developing drugs that can inhibit BAK and BAX. By targeting these key proteins, we hope to create new therapies that shield the heart during a heart attack, preserve its function, and ultimately save lives by limiting the loss of heart muscle cells.

Acute myocardial infarction (AMI) is a significant factor leading to the death of patients with coronary heart disease. Both AMI and reperfusion therapy after AMI cause myocardial cell death, which plays a significant role in heart failure. Following the restoration of blood flow during reperfusion, myocardial cells generate a large amount of oxygen free radicals, causing various forms of myocardial ischemia–reperfusion (IR) injury (IRI), ultimately leading to multiple types of myocardial cell death, among which apoptosis and necroptosis are the two major types. Given the extremely limited regenerative capacity of myocardium, inhibiting myocardial cell apoptosis and necroptosis is a key strategy for reducing mortality in patients with AMI. Both apoptosis and necroptosis are regulated by the BCL2 family of proteins, which were modulated by multiple signaling pathways, converging at BAK/BAX-mediated mitochondrial outer membrane permeabilization (MOMP), as well as mitochondrial inner membrane permeabilization (MIMP). BAK/BAX double knock out (DKO) mice showed reduced cell apoptosis, necroptosis, and infarct size in AMI animal models compared to wild type. This review describes the role of BCL2 family proteins in regulating apoptotic and necroptotic myocardial cell death during AMI and IR, explores the upstream pathways modulating apoptosis and necroptosis, and summarizes the recent advances in targeting BAK and/or BAX for cardiac protection. In addition, targeted delivery of BAK/BAX inhibitors to cardiomyocytes during AMI or myocardial IR has the potential to reduce myocardial cell death and therefore lower the mortality and enhance long-term prognosis for myocardial infarction patients.