217 Genetic ablation of microtubule-associated protein 1s (map1s) protects the heart from pathological hypertrophy via regulation of autophagy

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Abstract

Background

Autophagy is a process essential in maintaining cellular homeostasis, by degrading and recycling unwanted materials such as misfolded proteins and dysfunctional organelles. In the heart, autophagy is key in mediating pathological processes such as hypertrophy and remodelling. Autophagy is tightly regulated by a number of proteins and defective autophagy in response to pathological stimuli may lead to the development of adverse remodelling and eventually heart failure. In this study we investigated the role of microtubule-associated protein 1S (MAP1S) in regulating autophagy during a number of cardiac pathological conditions. MAP1S has previously been identified as an interacting partner of the major autophagy regulator LC3; however, its role in the heart is unknown.

Results

We used siRNA gene silencing to knockdown MAP1S in neonatal rat cardiomyocytes (NRCM) and detected the autophagic flux using GFP-LC3 expressing adenovirus. Following stimulation with rapamycin (5 uM) and chloroquine (3 uM) for 2 hours, NRCM lacking MAP1S exhibited an increase in autophagy as indicated by a significant elevation in GFP-LC3 puncta formation. To confirm this finding we cultured fibroblasts from MAP1S knock out (MAP1S-/-) mice and induced autophagy using the same stimulus. Consistently, MAP1S-/- fibroblasts also showed increased autophagy after rapamycin/chloroquine treatment. Interestingly, the expression of autophagic modulators LC3II, Beclin and p62 did not differ between cells lacking MAP1S and controls, suggesting that MAP1S might affect autophagosome elongation and not the initiation process. In vivo, we confirmed higher autophagy in MAP1S-/- mice following rapamycin/chloroquine intraperitoneal injection as indicated by the number of amphisomes detected by electron microscopy. Next, to test the effects of pathological stimuli we subjected MAP1S-/- mice to transverse aortic constriction (TAC, 2 weeks) or myocardial infarction (MI, 4 weeks). Following TAC, MAP1S-/- mice displayed less hypertrophy as indicated by heart weight/body weight ratio, cardiomyocyte surface area (histology) and the expression of hypertrophic markers. Consistently, after MI MAP1S-/- mice also showed a reduction in hypertrophy.

Conclusions

Our findings suggest that genetic inhibition of MAP1S induces autophagy in cardiomyocytes, whereas in vivo ablation of this gene in mice reduces cardiac hypertrophy in response to pathological stimuli such as TAC and MI.

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