Suppressed Nuclear Envelope Proteins Activate Autophagy Of Vascular Smooth Muscle Cells During Cyclic Stretch Application
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH(2021)
摘要
Dysfunctions of vascular smooth muscle cells (VSMCs) play crucial roles in vascular remodeling in hypertension, which correlates with pathologically elevated cyclic stretch due to increased arterial pressure. Recent researches reported that autophagy, a life-sustaining process, was increased in hypertension. However, the mechanobiological mechanism of VSMC autophagy and its potential roles in vascular remodeling are still unclear. Using renal hypertensive rats in vivo and FX5000 stretch application Unit in vitro, the autophagy of VSMCs was detected. The results showed that LC3II remarkably enhanced in hypertensive rats and 15% cyclic stretch (mimic the pathologically increased mechanical stretch in hypertension), and the activity of mammalian target of rapamycin (mTOR) was suppressed in 15% cyclic stretch. Administration of autophagy inhibitors, bafilomycin A1 and chloroquine, repressed VSMC proliferation efficiently, but did not affect the degradation of two important nuclear envelope (NE) proteins, lamin A/C and emerin. Using RNA interference to decline the expression of lamin A/C and emerin, respectively, we discovered that autophagy was upregulated under both static and 5% cyclic stretch conditions, accompanying with the decreased mTOR activity. During 15% cyclic stretch application, mTOR inhibition was responsible for autophagy elevation. Chloroquine administration in vivo inhibited the expression of PCNA (marker of proliferation) of abdominal aorta in hypertensive rats. Altogether, these results demonstrated that pathological cyclic stretch suppresses the expression of lamin A/C and emerin which subsequently represses mTOR pathway so as to induce autophagy activation. Blocking autophagic flux may be a practicable way to relieve the pathological vascular remodeling in hypertensive.
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关键词
Autophagy, Cyclic stretch, Nuclear envelope proteins, Mechanobiology, Vascular smooth muscle cells
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