Therapeutic targeting of autophagy in cardiovascular disease

Abstract

Autophagy is an evolutionarily ancient process of intracellular catabolism necessary to preserve cellular homeostasis in response to a wide variety of stresses. In the case of post-mitotic cells, where cell replacement is not an option, finely tuned quality control of cytoplasmic constituents and organelles is especially critical. And due to the ubiquitous and critical role of autophagic flux in the maintenance of cell health, it comes as little surprise that perturbation of the autophagic process is observed in multiple disease processes. A large body of preclinical evidence suggests that autophagy is a double-edged sword in cardiovascular disease, acting in either beneficial or maladaptive ways, depending on the context. In light of this, the autophagic machinery in cardiomyocytes and other cardiovascular cell types has been proposed as a potential therapeutic target. Here, we summarize current knowledge regarding the dual functions of autophagy in cardiovascular disease. We go on to analyze recent evidence suggesting that titration of autophagic flux holds potential as a novel treatment strategy.

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).…”

The role of autophagy in angiotensin II-induced pathological cardiac hypertrophy

“…The association between autophagic activity and heart disease has been noted for almost 40 years. Until now, a recurring paradox in the study of autophagy is its dual nature (Schiattarella & Hill 2016). In the heart, autophagy functions mainly as a pro-survival pathway during cellular stress by removing protein aggregates and damaged organelles, protecting the heart against famine, ischemia and excessive β-adrenergic stimulation.…”

“…In the heart, autophagy functions mainly as a pro-survival pathway during cellular stress by removing protein aggregates and damaged organelles, protecting the heart against famine, ischemia and excessive β-adrenergic stimulation. However, when severely triggered, the autophagic machinery may lead to cell death (Gatica et al 2015, Schiattarella & Hill 2016.…”

Protective effects of luteolin-7-O-glucoside against starvation-induced injury through upregulation of autophagy in H9c2 Cells

“…Autophagy may function primarily as a cytoprotective mechanism, to maintain nutrient and energy homeostasis during starvation conditions (7,8). However, activation of autophagy can also be harmful: excessive autophagy might cause undesirable cell death (9,10). Additional studies are needed to clarify whether autophagy activation serves as an adaptive or maladaptive cardiac response to starvation.…”