Autophagy is an important process to maintain cellular homeostasis in many cell types including cardiomyocytes. In the heart, defective autophagy in response to pathological stimuli may lead to the development of adverse remodelling and eventually heart failure. The microtubule-associated protein 1S (MAP1S) has previously been identified as an interacting partner of the major autophagy regulator LC3; however, its role in the heart is not completely understood. In this study we investigated the role of microtubule-associated protein 1S (MAP1S) in regulating autophagy during a number of cardiac pathological conditions.
siRNA gene silencing was used in Neonatal Rat Cardiomyocyte (NRCM) to knockdown MAP1S. The rate of autophagy was analysed using GFP-LC3 expressing adenovirus. This detection method was also used in fibroblast derived from MAP1S knock out mice (MAP1S -/-). Following rapamycin (5 uM) and chloroquine (3 uM) stimulation, both NRCM lacking MAP1S and Fibroblast derived from MAP1S knockout mice showed increased autophagy after 2 hours treatment compare to control. However, the expression level of p62 and beclin were not differ between NRCM lacking MAP1S, Fibroblast derived from MAP1S knockout mice and control. Interestingly, apoptosis as detected by TUNEL assay was significantly enhanced in NRCM lacking MAP1S.
To test the effect of pathological stimuli, we subjected MAP1S-/- mice to transverse aortic constriction (TAC, 2 weeks) or myocardial infarction (MI, 4 weeks). Following MI, we found a significantly higher mortality in MAP1S-/- mice (60%) vs WT control (30%) although the extent of MI was comparable between MAP1S-/- and WT as indicated by cTnI level and the fibrotic infarct area. TUNEL assay exhibited higher apoptosis in MAP1S-/- mice which might contribute to the low survival rate. The surviving MAP1S-/- mice showed reduction in hypertrophic response and consistent in the pressure overload and MI model as we found lower HW/BW ratio in MAP1S-/- mice. This phenotype might be attributable to higher autophagy in the knockout animals.
Our findings suggest that MAP1S modulates autophagy and apoptosis in cardiomyocytes. In vivo ablation of MAP1S might impair survival after MI and lead to an attenuated hypertrophic response following pressure overload.
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