Activation of MMP8 and MMP13 by angiotensin II correlates to severe intra-plaque hemorrhages and collagen breakdown in atherosclerotic lesions with a vulnerable phenotype

Cheng, Caroline; Tempel, Dennie; van Haperen, Rien; van Damme, Luc; Algür, Meryem; Krams, Rob; de Crom, Rini

doi:10.1016/j.atherosclerosis.2009.01.025

« Previous Next »Atherosclerosis
Volume 204, Issue 1 , Pages 26-33, May 2009

Activation of MMP8 and MMP13 by angiotensin II correlates to severe intra-plaque hemorrhages and collagen breakdown in atherosclerotic lesions with a vulnerable phenotype

Caroline Cheng
- Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands
Dennie Tempel
- Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands
- Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands
Rien van Haperen
- Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands
Luc van Damme
- Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands
Meryem Algür
- Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands
Rob Krams
- Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands
Rini de Crom
- Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands
- Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
- Corresponding author at: Erasmus MC, Room Ee1073, Dr. Molewaterplein 50, 3015 GD Rotterdam, The Netherlands. Tel.: +31 10 4087459; fax: +31 10 4089468.

Received 19 February 2008; received in revised form 14 January 2009; accepted 14 January 2009. published online 24 February 2009.

Abstract

Angiotensin II (ATII)-mediated hypertension increases the risk for acute coronary events, which may be caused by augmented collagen degradation. Interstitial fibers of collagen type I in the plaque can be degraded by MMP8 and MMP13 specifically. Indeed high MMP8 levels have been correlated with ruptured plaques in patients. To study the contribution of ATII in plaque rupture, we evaluated its effect on MMP8 and MMP13 activity on the vulnerable lesions using an extravascular device that induces regions of pro-atherogenic shear stress in the carotid arteries of ApoE KO mice. This triggers the growth of lesions with a “vulnerable” macrophage-rich phenotype (referred to as upstream lesions) and lesions with a “stable” fibrotic phenotype (referred to as downstream lesions).

ATII administration increased mean blood pressure, and increased the incidence of intra-plaque hemorrhages (IPH) from 30% to 73% of the animals in the upstream segments. The area of IPH was also increased by 5-fold. No IPHs were observed in the downstream lesions of the control group or the ATII group. In addition, ATII treatment doubled the size of upstream and downstream lesions. Upstream lesions in the ATII group were decreased in collagen content by 3-fold, contained 2-fold higher MMP8 and MMP13 levels, with a 2- and 3-fold increase in collagen type I degradation by MMP8 and MMP13 respectively compared to the upstream lesions in the control group. Gene expression analysis showed general increase in procollagens and TIMPs expression in response to ATII. However, ATII also decreased procollagen 5α3 expression in downstream lesions and decreased TIMP4 expression in upstream lesions.

These data show that ATII promotes a “stable” fibrotic phenotype by inducing severe intra-plaque hemorrhages, characterized by increased degradation of interstitial collagen I via an MMP-mediated (MMP8 and MMP13) mechanism.

Keywords: Angiotensin II, Atherosclerosis, Matrix metalloproteinase