Macrophage‐derived MMP‐9 enhances the progression of atherosclerotic lesions and vascular calcification in transgenic rabbits

Abstract

Matrix metalloproteinase-9 (MMP-9), or gelatinase B, has been hypothesized to be involved in the progression of atherosclerosis. In the arterial wall, accumulated macrophages secrete considerable amounts of MMP-9 but its pathophysiological functions in atherosclerosis have not been fully elucidated. To examine the hypothesis that macrophage-derived MMP-9 may affect atherosclerosis, we created MMP-9 transgenic (Tg) rabbits to overexpress the rabbit MMP-9 gene under the control of the scavenger receptor A enhancer/promoter and examined their susceptibility to cholesterol diet-induced atherosclerosis. Tg rabbits along with non-Tg rabbits were fed a cholesterol diet for 16 and 28 weeks, and their aortic and coronary atherosclerosis was compared. Gross aortic lesion areas were significantly increased in female Tg rabbits at 28 weeks; however, pathological examination revealed that all the lesions of Tg rabbits fed a cholesterol diet for either 16 or 28 weeks were characterized by increased monocyte/macrophage accumulation and prominent lipid core formation compared with those of non-Tg rabbits. Macrophages isolated from Tg rabbits exhibited higher infiltrative activity towards a chemoattractant, MCP-1 in vitro and R E FE R E N C E S 1. Gross J, Lapiere CM. Collagenolytic activity in amphibian tissues: a tissue culture assay. Additional supporting information may be found online in the Supporting Information section. How to cite this article: Chen Y, Waqar AB, Nishijima K, et al. Macrophage-derived MMP-9 enhances the progression of atherosclerotic lesions and vascular calcification in transgenic rabbits. J Cell Mol Med. 2020;24:4261-4274. https://doi.

Regulatory Role of Sex Hormones in Cardiovascular Calcification

“…However, studies have typically focused on male rabbits, with an extremely limited number of calcification studies including female animals. A recent study assessing both sexes in a matrix metallopeptidase 9 (MMP-9) overexpression model of atherosclerosis, revealed that both male and female rabbits developed calcified lesions in the aortic arch, with qualitative assessment suggesting greater calcification in males [ 153 ].…”

The Role of Matrix Metalloproteinase-9 in Atherosclerotic Plaque Instability

“…The inflammatory cells are the primary source of MMP-9 within the plaque [ 55 ]. Chen et al [ 56 ] reported that macrophage-derived MMP-9 could promote the infiltration of monocyte/macrophages into the lesions but had no effect on the fatty streak size. Only overexpression of the autoactivating form of MMP-9 in macrophages can induce significant plaque disruption [ 57 ].…”

Genetically Modified Rabbits for Cardiovascular Research

“…Until now, more than 20 kinds of Tg rabbits expressing different genes that are involved in lipid metabolism and atherosclerosis have been reported and studies using these Tg rabbits have provided considerable insights into the molecular mechanisms of these gene functions in lipoprotein metabolism and atherosclerosis (Fan and Watanabe, 2003 ; Peng, 2012 ; Fan et al, 2015 ). The transgenes expressed in Tg rabbits for the study of lipoprotein metabolism and atherosclerosis can generally be classified into three categories: (1) those proteins that constitute lipoprotein structures such as apo(a) (Rouy et al, 1998 ; Fan et al, 1999b ), apoAI (Duverger et al, 1996a ), apoAII (Koike et al, 2009a ; Wang et al, 2013 ), apoB-100 (Fan et al, 1995 ), apoCIII (Ding et al, 2011 ), and apoE (Huang et al, 1997 ; Fan et al, 1998 ); (2) those enzymes or transfer proteins that participate in the lipid metabolism such as hepatic lipase (Fan et al, 1994 ), lipoprotein lipase (Fan et al, 2001a ), phospholipid transfer protein (Masson et al, 2011 ), apoB-100 mRNA editing enzyme catalytic polypeptide protein (Yamanaka et al, 1995 ), lecithin:cholesterol acyltransferase (Hoeg et al, 1996 ), endothelial lipase (Wang et al, 2017 ); and (3) those proteins that may exert some functions on the arterial wall cells which participate in the pathogenesis of atherosclerosis including matrix metalloproteinase-1,9,12 (Liang et al, 2006 ; Niimi et al, 2019 ; Chen et al, 2020 ), 15-lipoxygenase (Shen et al, 1996 ), C-reactive protein (Koike et al, 2009b ), and vascular endothelial growth factor (Kitajima et al, 2005 ) ( Table 1 ). In addition, Tg rabbits have also been used for the investigation of human heart diseases, including LQT syndrome (Brunner et al, 2008 ), hypertrophic cardiomyopathy (Marian et al, 1999 ) and tachycardia-induced cardiomyopathy (Suzuki et al, 2009 ).…”