Published Online
on October 22, 2007

A more recent version of this article appeared on November 6, 2007

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Submitted on March 27, 2007
Accepted on September 6, 2007

Normal Vascular Function Despite Low Levels of High-Density Lipoprotein Cholesterol in Carriers of the Apolipoprotein A-I_Milano Mutant

Monica Gomaraschi PhD, Damiano Baldassarre PhD, Mauro Amato PhD, Sonia Eligini PhD, Paola Conca PhD, Cesare R. Sirtori MD, PhD, Guido Franceschini PhD^*, and Laura Calabresi PhD

From the Center E. Grossi Paoletti (M.G., D.B., S.E., P.C., C.R.S., G.F., L.C.), Department of Pharmacological Sciences, University of Milano, and the Center Cardiologico Monzino (D.B., M.A.), Istituti di Ricovero e Cura Carattere Scientifico (IRCCS), Milan, Italy.

^* To whom correspondence should be addressed. E-mail: Guido.Franceschini{at}unimi.it.

Background—Carriers of the apolipoprotein A-I_Milano (apoA-I_M) mutant have very low plasma high-density lipoprotein cholesterol (HDL-C) levels but do not show any history of premature cardiovascular disease or any evidence of preclinical vascular disease. HDL is believed to prevent the development of vascular dysfunction, which may well contribute to HDL-mediated atheroprotection. Whether the low HDL level of apoA-I_M carriers is associated with impaired vascular function is presently unknown.

Methods and Results—The vascular response to reactive hyperemia, assessed by measuring postischemic increase in forearm arterial compliance, and the plasma concentration of soluble cell adhesion molecules were evaluated in 21 adult apoA-I_M carriers, 21 age- and gender-matched nonaffected relatives (control subjects), and 21 healthy subjects with low HDL-C (low-HDL subjects). The average plasma HDL-C and apoA-I levels of apoA-I_M carriers were remarkably lower than those of control subjects and significantly lower than those of low-HDL subjects. The postischemic increase in forearm arterial compliance in the apoA-I_M carriers was 2-fold greater than in low-HDL subjects and remarkably similar to that of control subjects. Plasma soluble cell adhesion molecule levels were similar in apoA-I_M carriers and control subjects but were greater in low-HDL subjects. When incubated with endothelial cells, HDL isolated from apoA-I_M carriers was more effective than HDL from control and low-HDL subjects in stimulating endothelial nitric oxide synthase expression and activation and in downregulating tumor necrosis factor-–induced expression of vascular cell adhesion molecule-1.

Conclusions—Despite their very low HDL levels, apoA-I_M carriers do not display typical features of impaired vascular function because of an improved activity of apoA-I_M HDL in maintaining endothelial cell homeostasis.

Key words: lipoproteins • apolipoproteins • vasodilation • nitric oxide • cell adhesion molecules

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