심장비대증에서 저밀도지단백수용체 연관 단백질-1의 역할 규명

Abstract

Cardiac hypertrophy is one of risk factors associated with heart failure which is the number one cause of death worldwide. Since it has been reported that α₂-macroglobulin induces cardiomyocyte hypertrophy, we hypothesized that a reduction of low density lipoprotein receptor-related protein 1 (LRP1) would decrease cardiac hypertrophy induced by catecholamines such as, phenylephrine (PE) and norepinephrine (NE). We confirmed that cell size and protein/DNA ratio were increased in PE- or NE-treated neonatal rat cardiomyocytes (NRCM). First, we observed that the expression levels of LRP1 were significantly increased in PE- or NE-treated NRCM by ~ 3 or ~ 2 folds, respectively, higher than non-treated controls. The mRNA levels of hypertrophic markers such as, ANF, BNP, β-MHC, and HPRT were also significantly increased in PE- or NE-treated NRCM. In order to investigate the role of LRP1 in cardiac hypertrophy, we silenced LRP1 by specific siRNA molecules. We could observe the ~ 70 % down-regulation of LRP1 expression and cell area were successfully rescued to normal levels in LRP1 siRNA transfected NRCM with PE or NE. The increased protein/DNA ratio by PE- or NE-treatment was also decreased to normal values in LRP1 siRNA co-treated NRCM. In addition, we observed that the LRP1 expression level was upregulated in the after 4 ~ 5 weeks of transverse aortic constriction surgery. Our results suggest that LRP1 has a critical role in catecholamine-induced cardiac hypertrophy, which might be a potential target for treatment of cardiac hypertrophy.