Submitted on August 3, 2005
Revised on December 14, 2005
Accepted on December 21, 2005
Interaction between mild hypercholesterolemia, reduced HDL-cholesterol levels and angiotensin II on intimal hyperplasia development in mice
Valdeci da Cunha, Baby Martin-McNulty, Jon Vincelette, Lening Zhang, John C. Rutledge, Dennis W. Wilson, Ronald Vergona, Mark E. Sullivan, and Yi-Xin (Jim) Wang
Pharmacology dDept., Berlex Biosciences, Richmond, CA 94806
Corresponding Author: valdeci_dacunha{at}yahoo.com
In the present study we assessed the interaction between mild hypercholesterolemia and angiotensin (Ang) II on intimal smooth muscle cell (SMC) proliferation following carotid artery ligation. Two month-old C57BL/6 mice were placed on three different diets: 1) normal diet (NC: 6% fat, 0.025% cholesterol), 2) hypercholesterolemic Western-type diet (HC-W: 20% fat, 0.2% cholesterol) and 3) hypercholesterolemic Paigen-type diet (HC-P: 15% fat, 1.25% cholesterol plus 0.5% cholic acid). At six months of age, the animals underwent ligation of the left common carotid artery (5-0 silk suture), and were randomly assigned to receive either vehicle (PBS, sc) or Ang II (1.4 mg.kg-1.day-1, sc) via an osmotic infusion pump for four weeks. Low-density lipoprotein-cholesterol (LDL-C) levels were similarly elevated in both hypercholesterolemic diets (NC: 4+/-3 mg/dL; HC-W: 123+/-17 mg/dL; HC-P: 160+/-14 mg/dL). However, the levels of high-density lipoprotein-cholesterol (HDL-C) was significantly reduced only in animals fed the HC-P diet (NC: 82+/-6 mg/dL; HC-W: 79+/-7 mg/dL; HC-P: 58+/-7 mg/dL), resulting in a 2.3-fold increase in LDL-C/HDL-C ratio in relation to the HC-W diet (HC-W:1.6+/-0.3; HC-P: 3.7+/-1.2, P<0.05). None of the animals on NC diet developed intimal hyperplasia following carotid artery ligation, in contrast with 1 in 7 mice fed the HC-W diet and 3 in 6 fed the HC-P diet. In Ang II-treated mice, carotid artery ligation induced intimal SMC proliferation to a similar extent in NC and HP-W fed animals. However, a significantly larger intimal area developed in ligated vessels from Ang II-treated mice fed the HC-P diet (3.6-fold higher than Ang II-treated NC mice). Together, the present study shows the accelerating effect of mild hypercholesterolemia, reduced HDL-C levels and Ang II on intimal hyperplasia development in hemodynamically altered vessels.
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