MDR1 Gene Expression in Normal and Atherosclerotic Human Arteries<footref rid="foot01">¹</footref>

Abstract

Recent studies have shown that a membrane p-glycoprotein, encoded by MDR1 gene, is involved in the transport of free cholesterol from the plasma membrane to endoplasmic reticulum, the site of cholesterol esterification by acyl-CoA:cholesterol acyltransferase (ACAT). Moreover, results deriving from our previous studies have shown that the rate of cell proliferation was positively correlated with cholesteryl ester levels as well as with ACAT and MDR1 gene expression. In this study, lipid content and the expression of the genes involved in cholesterol metabolism such as hydroxy-methylglutaryl coenzyme A reductase (HMGCoA-R), low-density lipoprotein receptor (LDL-R), ACAT and MDR1 have been investigated in control and atherosclerotic arteries. The results have shown that the levels of cholesteryl ester increase with the age of cadaveric donors in arteries prone to atherosclerosis (abdominal aorta, superficial femoral artery) and become predominant in advanced atherosclerotic lesions. The mRNA levels of ACAT and MDR1 showed the same age correlation, reaching the highest values in atherosclerotic specimens. These results suggest that MDR1 may be involved in the accumulation of intracellular cholesterol ester levels found in atherosclerotic lesions. Moreover, the levels of HMGCoA-R, LDL-R and ACAT gene expressions progressively increased with the age of cadaveric donors; conversely, in atherosclerotic specimens, the mRNA levels of HMGCoA-R and LDL-R drastically decreased while ACAT gene expression reached its maximum. These findings suggest a reactivation of normal homeostatic regulation of cholesterol in advanced and complicated lesions.

The Effect of Age on P-Glycoprotein Expression and Function in the Fischer-344 Rat

“…Lown et al (1997) found no change in age in intestinal P-gp expression in 25 renal patients between 21 and 67 years of age, whereas Batetta et al (1999) found that MDR1 mRNA expression was increased in the atherosclerotic plaques of elderly subjects.…”

Cholesterol Esterification as a Mediator of Proliferation of Vascular Smooth Muscle Cells and Peripheral Blood Mononuclear Cells during Atherogenesis

“…It is well known that CE accumulation is mainly due to two independent processes: the conversion of free cholesterol (FC) into CEs by acyl-CoA-cholesterol transferase 1 (ACAT-1) and the degradation of CEs into FC and free fatty acids by the neutral cholesterol ester hydrolase (n-CEH). We have previously reported that CEs play a critical role in the control of the G1/S transition of the human VSMC cell cycle [15,16,17,18]: thymidine incorporation into DNA in serum-stimulated VSMCs was preceded by an increase in the rate of cholesterol esterification. CE inhibitors were able to prevent proliferation of VSMCs by blocking the progression of the cell cycle from the G1 to the S phase.…”

Associations between common 3435 C>T variants of the multi-drug resistance [MDR-1 (ABCB1)] gene and abdominal aortic aneurysm: a pilot study

“…[9] The expression of P-gp, a transport protein dependent on ATP, is decreased when there is a single nucleotide polymorphism in 26 th exon of the MDR-1 gene. [10][11][12] Furthermore, the evidence of previous studies has shown that cholesterol ester level binding to MDR-1 gene expression is positively correlated with cellular proliferation. [10] Besides it has been shown that MDR-1 was observed in pathologies that affect the vessel wall such as atherosclerosis.…”

“…[10][11][12] Furthermore, the evidence of previous studies has shown that cholesterol ester level binding to MDR-1 gene expression is positively correlated with cellular proliferation. [10] Besides it has been shown that MDR-1 was observed in pathologies that affect the vessel wall such as atherosclerosis. [10] In this study we aimed to investigate the relationship between MDR-1 gene polymorphism and AAA.…”

“…[10] Besides it has been shown that MDR-1 was observed in pathologies that affect the vessel wall such as atherosclerosis. [10] In this study we aimed to investigate the relationship between MDR-1 gene polymorphism and AAA.…”