Association between intracerebral hemorrhage and cholesterol levels, and molecular mechanism underlying low cholesterol inhibiting autophagy in cerebral arterial smooth muscle cells leading to cell necrosis

Abstract

BackgroundAn association between cholesterol and intracerebral hemorrhage (ICH) has been reported, but the mechanism is unclear. MethodsIn this cross-sectional study, participants aged 50–75 years were selected using multistage stratified cluster sampling. All samples completed a questionnaire (age, gender, medication, etc.) and were examined (blood lipid, height, blood pressure, etc.) for risk factors. Multivariable logistic regression was used to analyze the association between cholesterol levels and ICH risk, after adjusting for age, smoking, hypertension, and other factors. We cultured rat cerebral artery smooth muscle cells at different cholesterol concentrations. The autophagy pathway was identified by transcriptome sequencing. The results were then validated using real-time polymerase chain reaction and western blot. ResultsWe included 39,595 patients, among whom 286 had ICH. The study showed that a low level of low-density lipoprotein cholesterol (LDL-C) was a risk factor of ICH (odds ratio 2.912, 95% confidence interval 1.460–5.806; P = 0.002). Cell experiments showed that lower cholesterol levels could significantly induce rat cerebral artery smooth muscle cell necrosis. In low-cholesterol groups, expression of the autophagy marker LC3 protein was significantly decreased and p62 protein was significantly increased. In western blot and comparison with the control group, the low cholesterol PI3K/Akt/mTOR signaling pathway was significantly activated in the autophagy pathway, resulting in its inhibition, which in turn led to smooth muscle cell death. ConclusionLow cholesterol levels may inhibit autophagy through PI3K/Akt/mTOR signaling and induce arterial smooth muscle cell necrosis, thereby increasing the risk of ICH.