Autophagy in hypertensive heart disease

Abstract

In response to hypertension, the heart manifests robust hypertrophic growth, which offsets load-induced elevations in wall stress. If sustained, this hypertrophic response is a major risk factor for systolic dysfunction and heart failure. Extensive research efforts have focused on the progression from hypertrophy to failure; however, precise understanding of underlying mechanisms remains elusive. Recently, autophagy, a process of cellular cannibalization, has been implicated. Autophagy is activated during ventricular hypertrophy, serving to maintain cellular homeostasis. Excessive autophagy eliminates, however, essential cellular elements and possibly provokes cell death, which together contribute to hypertension-related heart disease.

FIGURE 1.

Autophagic machinery. In the absence of the suppressive influence of TOR kinase, dephosphorylated ATG13 interacts with ATG1 and ATG17, forming a kinase complex that initiates autophagy. The class III PI3K complex comprises the lipid kinase Vps34, the regulatory subunits Beclin 1/ATG6 and ATG14, and Vps15, which together generate phosphatidylinositol 3-phosphate, leading to nucleation of the autophagosome. Following this, two ubiquitin-like conjugation systems generate ATG16-ATG5-ATG12 and LC3-II-PE complexes, expanding the phagophore and forming the autophagosome. Before fusion with a lysosome to form an autolysosome, most ATG proteins are recycled under the regulation of ATG9 and ATG18. Beclin 1/ATG6 also interacts with UVRAG, Vps34, and Vps15 to form another complex, which is involved in the maturation and trafficking of the autophagosome. Hydrolases within the lysosome degrade the inner membrane of autophagosome and the engulfed cargo. The resulting constituents, including sugars, amino acids, and lipids, are then released to the cytosol. IGF1, insulin-like growth factor 1; 3-MA, 3-methyladenine.

FIGURE 2.

Model of the role(s) of autophagy in hypertensive heart disease. In the basal state, constitutive levels of autophagy are required for cell survival, especially in post-mitotic cells that must survive decades without replication. Near-total inactivation of autophagic activity is maladaptive, promoting cell death. Conversely, less drastic decreases (or conversely, increases) in autophagic activity are not associated with untoward events. In the setting of growth stimulation, both anabolic and catabolic processes are activated. During the initial phase, the former predominates, and cell growth ensues. In fact, some evidence suggests that the catabolic autophagic pathway may be transiently suppressed in early phases of growth. Ultimately, however, a new steady state emerges where levels of autophagic flux are increased. Depending on the strength of the growth stimulus (and the genetic context where autophagy is suppressed either completely or partially or amplified), the resulting autophagic activity is either adaptive or maladaptive. In some contexts, hypoxia may contribute to the induction of maladaptive autophagy, as well. WT, wild type; Tg, transgenic.