Autophagy modulation: a potential therapeutic approach in cardiac hypertrophy

Abstract

Autophagy is an evolutionarily conserved process used by the cell to degrade cytoplasmic contents for quality control, survival for temporal energy crisis, and catabolism and recycling. Rapidly increasing evidence has revealed an important pathogenic role of altered activity of the autophagosome-lysosome pathway (ALP) in cardiac hypertrophy and heart failure. Although an early study suggested that cardiac autophagy is increased and that this increase is maladaptive to the heart subject to pressure overload, more recent reports have overwhelmingly supported that myocardial ALP insufficiency results from chronic pressure overload and contributes to maladaptive cardiac remodeling and heart failure. This review examines multiple lines of preclinical evidence derived from recent studies regarding the role of autophagic dysfunction in pressure-overloaded hearts, attempts to reconcile the discrepancies, and proposes that resuming or improving ALP flux through coordinated enhancement of both the formation and the removal of autophagosomes would benefit the treatment of cardiac hypertrophy and heart failure resulting from chronic pressure overload.

TFEB activation protects against cardiac proteotoxicity via increasing autophagic flux

“…When mTORC1 is inactivated, TFEB phosphorylation by mTORC1 stops and concomitantly phosphatase calcineurin is activated to dephosphorylate TFEB, in which calcineurin activation is triggered by the release of lysosomal Ca 2+ via the Ca 2+ channel mucolipin 1 (MCOLN1). The dephosphorylated TFEB can then enter the nucleus and activate the transcription of an entire network of genes that are essential to and orchestrate lysosomal biogenesis and autophagy [4]. Here we discovered that the myocardial mRNA levels of all examined representative TFEB target genes involved respectively in autophagy ( Vps18 and Uvrag ) and lysosomal biogenesis ( M6pr and Mcoln1 ) were significantly decreased in the CryAB R120G mice (Figure 2B, 2C).…”

“…However, this increased TFEB mRNA and TFEBb protein expression were not translated into an increased TFEB activity because the steady state mRNA levels of all examined TFEB target genes including Mcoln1 , M6pr , Vps18 and Uvrag were significantly and uniformly down-regulated in the CryAB R120G tg mouse hearts (Figure 2B, 2C), indicating that TFEB activation is suppressed in the heart with advanced cardiac proteinopathy. Phosphorylation of TFEB by mTORC1 (mechanistic target of rapamycin complex 1) is a mechanism that sequesters TFEB in the cytoplasm and thereby suppresses TFEB activation [4]. To explore the underlying cause of suppressed TFEB signaling in the proteinopathic hearts, we assessed myocardial mTORC1 activity.…”

“…TFEB phosphorylation status determines its subcellular localization and activity. mTORC1 is a major upstream kinase that phosphorylates TFEB at multiple critical serine residues, which enables the chaperone 14-3-3 to bind TFEB and thereby sequesters TFEB in the cytoplasm where TFEB can co-localize with mTOR at the surface of lysosomes [4]. When mTORC1 is inactivated, TFEB phosphorylation by mTORC1 stops and concomitantly phosphatase calcineurin is activated to dephosphorylate TFEB, in which calcineurin activation is triggered by the release of lysosomal Ca 2+ via the Ca 2+ channel mucolipin 1 (MCOLN1).…”

“…By contrast, the ALP degrades cellular content in a bulky fashion and thereby plays an important role in the quality control of not only proteins but also organelles such as mitochondria. Terminally misfolded proteins, when escaped from or overwhelmed the surveillance of chaperones and the UPS, undergo aggregation via hydrophobic interaction and form aberrant aggregates which are inaccessible by the proteasome and can only be degraded by macroautophagy [3, 4]. Hence, the ALP plays a critical role in PQC.…”

Activation of IGF-1 receptors and Akt signaling by systemic hyperinsulinemia contributes to cardiac hypertrophy but does not regulate cardiac autophagy in obese diabetic mice

“…Similarly, enhancement of autophagy using resveratrol restored cardiac diastolic function, while inhibition of autophagy using chloroquine worsened both cardiac diastolic and systolic function in leptin receptor-deficient ( db/db ) mice [39]. Furthermore, autophagy insufficiency occurs in sustained cardiac hypertrophy as seen in chronic left ventricular hypertrophy and recent reports suggest that improving autophagy could alleviate cardiac hypertrophy [47]. Therefore, we predicted that autophagy restoration in the hearts of obese T2DM mice will be beneficial for cardiac structure and function and further inhibition will be detrimental.…”