Therapeutic targeting of autophagy in myocardial infarction and heart failure

Abstract

PubMed searches were performed to discuss the current state of the art regarding the role of autophagy in MI and HF. We review available and potential approaches to modulate autophagy from a pharmacological and genetic perspective. We also discuss the targeting of autophagy in myocardial regeneration. Expert commentary: The targeting of autophagy has potential for the treatment of MI and HF. Autophagy is a process that takes place in virtually all cells of the body and thus, in order to evaluate this therapeutic approach in clinical trials, strategies that specifically target this process in the myocardium is required to avoid unwanted effects in other organs.

Autophagy Activation in Zebrafish Heart Regeneration

“…Heart failure is regarded a global pandemic that affects about 26 million people around the globe 33 . It is therefore a priority to find novel therapeutic approaches that protect the cardiac tissue, improve the healing outcome, and prevent the pathological progression from an acute myocardial injury to a chronic disease 14,15 . In this regard, autophagy is a homeostatic process that can be activated to prevent cell death and provide metabolic substrates under stress conditions.…”

“…Transmission electron microscopy. At 3,7,14, and 28 dpa (N ≥ 3) zebrafish were euthanized and regenerating hearts were dissected. Uninjured hearts from sibling zebrafish were used as controls.…”

“…On the other hand, autophagy has been found to be involved in the onset and progression of many cardiovascular diseases, such as myocardial infarction and chronic heart failure, where it is a riddle how autophagy may have a protective role, while at the same time, aggravating cardiac dysfunction 12,13 . Because of this, autophagy has been recognized as a potential therapeutic target for cardiovascular diseases, though finding the right strategy to use autophagy activation to improve clinical outcome has not been possible until now 14,15 .The zebrafish (Danio rerio) has become a popular vertebrate model organism because of its superb regenerative capacities. Experimental models of heart amputation 16 , cardiomyocyte-specific genetic ablation 17 , hypoxic damage and ischemia/reperfusion injury 18,19 have all shown that, contrary to adult mammals, the zebrafish is capable of restoring damaged and lost myocardial tissue regardless of its age 20,21 .…”

“…On the other hand, autophagy has been found to be involved in the onset and progression of many cardiovascular diseases, such as myocardial infarction and chronic heart failure, where it is a riddle how autophagy may have a protective role, while at the same time, aggravating cardiac dysfunction 12,13 . Because of this, autophagy has been recognized as a potential therapeutic target for cardiovascular diseases, though finding the right strategy to use autophagy activation to improve clinical outcome has not been possible until now 14,15 .…”

Uromodulin p.Cys147Trp mutation drives kidney disease by activating ER stress and apoptosis

“…Both drugs enhanced clearance of the aggregated mutant form of UMOD p.Cys147Trp in the in vitro assay and therefore may be an attractive approach for treating UAKD. Pharmacological approaches to augment autophagy and regulate mTOR are in development for many disease indications, including neuropathies, kidney disease, cardiovascular disease, immune thrombocytopenia, and colorectal cancer, among others (86)(87)(88)(89)(90)(91). Of note, patients with autosomal dominant polycystic kidney disease (ADPKD) in the SIRENA study who received a 6-month treatment of sirolimus (rapamycin) added to conventional therapy experienced halted growth of kidney cysts, with no observed serious adverse events (91).…”