Abstract
Rapamycin, also known as sirolimus, is an antifungal agent and immunosuppressant drug used to prevent organ rejection in transplantation. However, little is known about the role of rapamycin in cardiac hypertrophy and the signaling pathways involved. Here, the effect of rapamycin was examined using phenylephrine (PE) induced cardiomyocyte hypertrophy in vitro and in a rat model of aortic banding (AB) - induced hypertrophy in vivo. Inhibition of MEK/ERK signaling reversed the effect of rapamycin on the up-regulation of LC3-II, Beclin-1 and Noxa, and the down-regulation of Mcl-1 and p62. Silencing of Noxa or Beclin-1 suppressed rapamycin-induced autophagy, and co-immunoprecipitation experiments showed that Noxa abolishes the inhibitory effect of Mcl-1 on Beclin-1, promoting autophagy. In vivo experiments showed that rapamycin decreased AB-induced cardiac hypertrophy in a MEK/ERK dependent manner. Taken together, our results indicate that rapamycin attenuates cardiac hypertrophy by promoting autophagy through a mechanism involving the modulation of Noxa and Beclin-1 expression by the MEK/ERK signaling pathway.
Highlights
Cardiac hypertrophy is an enlargement of the heart in response to different pathological stimuli such as hypertension, myocardial ischemia, and endocrine disorders (Frey and Olson, 2003)
We showed that rapamycin attenuates cardiac hypertrophy by inducing autophagy and elucidated a potential underlying mechanism involving MEK/ERK12 signaling and the modulation of the expression of Noxa and Beclin-1
An inhibitor of mammalian target of rapamycin (mTOR), inhibits cardiac hypertrophy, as determined by the downregulation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in cardiomyocytes, and promotes autophagy via the up-regulation of Beclin-1 and Noxa and the down-regulation of p62 and Mcl-1, suggesting that rapamycin exerts a protective effect on cardiomyocytes via the induction of autophagy
Summary
Cardiac hypertrophy is an enlargement of the heart in response to different pathological stimuli such as hypertension, myocardial ischemia, and endocrine disorders (Frey and Olson, 2003). The mechanisms underlying cardiac hypertrophy have been investigated to improve the design of therapeutic strategies for the treatment of heart failure, and recent studies have suggested a link between autophagy dysregulation and cardiac hypertrophy (Li et al, 2015). A catabolic process by which cytosolic proteins are degraded in the lysosome, plays important roles in cellular homeostasis, development, and defense mechanisms (Wang et al, 2009). Autophagy plays a dual role as a pro- and anti-survival process, and dysregulation of autophagy is associated with several diseases including cancer, neurodegeneration, and cardiomyopathy (Maiuri et al, 2007; Levine and Kroemer, 2008). Autophagy is increased in heart failure associated with dilated cardiomyopathy, ischemic heart disease, and valvular disease, whether autophagy
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