Autophagy as a therapeutic target in cardiovascular disease

Abstract

The epidemic of heart failure continues apace, and development of novel therapies with clinical efficacy has lagged. Now, important insights into the molecular circuitry of cardiovascular autophagy have raised the prospect that this cellular pathway of protein quality control may be a target of clinical relevance. Whereas basal levels of autophagy are required for cell survival, excessive levels - or perhaps distinct forms of autophagic flux - contribute to disease pathogenesis. Our challenge will be to distinguish mechanisms that drive adaptive versus maladaptive autophagy and to manipulate those pathways for therapeutic gain. Recent evidence suggests this may be possible. Here, we review the fundamental biology of autophagy and its role in a variety of forms of cardiovascular disease. We discuss ways in which this evolutionarily conserved catabolic mechanism can be manipulated, discuss studies presently underway in heart disease, and provide our perspective on where this exciting field may lead in the future. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.''

Figure 1. Therapeutic manipulation of core autophagic machinery

Therapeutic agents that target specific molecular components of the core autophagic machinery. Abbreviations: TSA – Trichostatin A; SAHA – Suberoylanilide hydroxamic acid; ROS – reactive oxygen species

Figure 2. Main regulatory pathways governing autophagy

Simplified scheme of the major cellular pathways governing autophagic responses in ventricular cardiomyocytes. See text for details. Arrow denotes stimulation, and T-shaped indicators denote inhibition.

Figure 3. Relationship between autophagic flux activity and myocardial function

Working model of instances where changes in cardiac function (expressed as % fractional shortening, FS) were associated with alterations in autophagic flux. 1) WT – wild type; 2) cryAB^R120G – αB-crystallin mutant; 3) starvation – 48 h food deprivation; 4) Beclin 1 −/− knockout; 5) CryAB^WT – over-expresser of WT αB-crystallin, Autophagy-related gene (Atg) 5 and 7 knockout; 6) TAC – afterload stress induced in WT mice by thoracic aortic constriction; 7) forkhead box transcription factors, O FoxO1 knockout, FoxO3 knockout; 8) sTAC – severe TAC, MI – myocardial infarction induced in WT mice by ligation of left anterior descending artery. FoxO3 – constitutive over-expression of FoxO3;

Figure 4. Therapeutic manipulation of cardiac autophagy

Targeting cardiac autophagy using FDA-approved therapeutics could be accomplished by direct regulation of the core autophagic machinery (Figure 1) or by manipulation of key upstream regulatory pathways (Figure 2 and Table 1) (see text for details).