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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1277.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Acute Elevation of Plasma PLTP Activity Strongly Increases Pre-existing Atherosclerosis

Matthijs Moerland; Hannelore Samyn; Teus van Gent; Rien van Haperen; Geesje Dallinga-Thie; Frank Grosveld; Arie van Tol; Rini de Crom

From the Department of Cell Biology & Genetics (M.M., H.S., T.v.G., R.v.H., F.G., A.v.T., R.d.C.), Erasmus University Medical Center, Rotterdam; the Department of Vascular Medicine (G.D.-T.), AMC, Amsterdam; and the Department of Vascular Surgery (R.d.C.), Erasmus Medical University Center, Rotterdam, The Netherlands.

Correspondence to Rini de Crom, PhD, Department Cell Biology & Genetics/Vascular Surgery, Erasmus University Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail m.decrom{at}erasmusmc.nl

Objective— A transgenic mouse model was generated that allows conditional expression of human PLTP, based on the tetracycline-responsive gene system, to study the effects of an acute increase in plasma PLTP activity as may occur in inflammation.

Methods and Results— The effects of an acute elevation of plasma PLTP activity on the metabolism of apolipoprotein B–containing lipoproteins and on diet-induced pre-existing atherosclerosis were determined in mice displaying a humanized lipoprotein profile (low-density lipoprotein receptor knockout background). Induced expression of PLTP strongly increases plasma VLDL levels in LDL receptor knockout mice, whereas VLDL secretion is not affected. The elevation in plasma triglyceride levels is explained by a PLTP-dependent inhibition of VLDL catabolism, which is caused, at least partly, by a decreased lipoprotein lipase activity. Together with the decreased plasma HDL levels, the acutely increased PLTP expression results in a highly atherogenic lipoprotein profile. Induction of PLTP expression leads to a further increase in size of pre-existing atherosclerotic lesions, even on a chow diet. In addition, the lesions contain more macrophages and less collagen relative to controls, suggesting a less stable lesion phenotype.

Conclusion— In conclusion, acute elevation of PLTP activity destabilizes atherosclerotic lesions and aggravates pre-existing atherosclerosis.

In LDL receptor knockout mice with conditional expression of human PLTP plasma VLDL levels are strongly increased, whereas VLDL secretion is not affected. This is explained by a PLTP-dependent inhibition of VLDL catabolism. After PLTP induction, preexisting atherosclerotic lesions grow larger, even on a chow diet. In addition, the lesions show a less stable phenotype.

Key Words: atherosclerosis • lipoproteins • phospholipid transfer protein • transgenic mouse models • triglycerides