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Review
. 2016 Jun:95:86-93.
doi: 10.1016/j.yjmcc.2015.11.019. Epub 2015 Nov 18.

Therapeutic targeting of autophagy in cardiovascular disease

Gabriele G Schiattarella  1 , Joseph A Hill  2
Affiliations
Review

Therapeutic targeting of autophagy in cardiovascular disease

Gabriele G Schiattarella et al. J Mol Cell Cardiol. 2016 Jun.

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.

Keywords: Cardiac hypertrophy; Heart failure; Remodeling.

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Conflict of interest statement

Conflicts of Interest

We declare no conflicts of interest.

Figures

Figure 1
Figure 1. Autophagy as a homeostatic response within the cardiovascular system
In response to disease-related cardiovascular stress, a number of systemic responses are triggered which support cardiovascular performance in the short term. Those same responses, when allowed to persist, are maladaptive. Indeed, antagonism of the β-adrenergic and renin-angiotensin-aldosterone (RAAS) pathways is a cornerstone of HF therapy. Emerging evidence suggests that both autophagy and LVH act similarly in their short-term and long-term actions. We speculate that each may emerge with time as a target of therapy. LVH: left ventricular hypertrophy.
Figure 2
Figure 2. The double-edged sword of autophagic flux
Autophagic activity is beneficial when maintained within a narrow range. When flux is activated to high levels, or suppressed to low levels, the process is maladaptive.
Figure 3
Figure 3. Autophagic flux kinetics during ischemia/reperfusion injury
During ischemia, when a cell is “starved”, autophagy is activated. With time, however, autophagic flux during ischemia declines below baseline, possibly owing to inadequate ATP availability. During reperfusion, replenishment of O2 and nutrients is coupled with ER (endoplasmic reticulum) stress, accumulation of reactive oxygen species (ROS), Ca2+ mishandling and mitochondrial dysfunction. Autophagic flux remains low.
Figure 4
Figure 4. Working model of potential therapeutic manipulation of autophagy in cardiovascular disease
Whereas the field is still evolving, we propose the following as therapeutic objectives in titrating cardiomyocyte autophagy in heart disease. LVH: left ventricular hypertrophy; HFrEF: heart failure with reduced ejection fraction; HFpEF: heart failure with preserved ejection fraction.
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