Abstract
Matrix metalloproteinase (MMP) activity is tightly regulated by the endogenous tissue inhibitors (TIMPs), and dysregulated activity contributes to extracellular matrix remodelling. Accordingly, MMP/TIMP balance is associated with atherosclerotic plaque progression and instability, alongside adverse post-infarction cardiac fibrosis and subsequent heart failure. Here, we demonstrate that prolonged high-fat feeding of apolipoprotein (Apo)e-deficient mice triggered the development of unstable coronary artery atherosclerosis alongside evidence of myocardial infarction and progressive sudden death. Accordingly, the contribution of select MMPs and TIMPs to the progression of both interrelated pathologies was examined in Apoe-deficient mice with concomitant deletion of Mmp7, Mmp9, Mmp12, or Timp1 and relevant wild-type controls after 36-weeks high-fat feeding. Mmp7 deficiency increased incidence of sudden death, while Mmp12 deficiency promoted survival, whereas Mmp9 or Timp1 deficiency had no effect. While all mice harboured coronary disease, atherosclerotic burden was reduced in Mmp7-deficient and Mmp12-deficient mice and increased in Timp1-deficient animals, compared to relevant controls. Significant differences in cardiac fibrosis were only observed in Mmp-7-deficient mice and Timp1-deficient animals, which was associated with reduced capillary number. Adopting therapeutic strategies in Apoe-deficient mice, TIMP-2 adenoviral-overexpression or administration (delayed or throughout) of a non-selective MMP inhibitor (RS-130830) had no effect on coronary atherosclerotic burden or cardiac fibrosis. Taken together, our findings emphasise the divergent roles of MMPs on coronary plaque progression and associated post-MI cardiac fibrosis, highlighting the need for selective therapeutic approaches to target unstable atherosclerosis alongside adverse cardiac remodelling while negating detrimental adverse effects on either pathology, with targeting of MMP-12 seeming a suitable target.
Highlights
A wide range of cardiovascular pathologies including, but not limited to, atherosclerotic plaque progression and rupture, and ensuing adverse post-myocardial infarction (MI) remodelling are highly dependent on extracellular matrix (ECM) turnover[1]
We have previously demonstrated that modulation of Matrix metalloproteinase (MMP) expression and/or activity using the approaches detailed within this study affects atherosclerosis within the brachiocephalic artery of short-term (8–10 weeks) high-fat fed Apoe−/− mice[5,13,20]
Specific MMP/tissue inhibitors of metalloproteinases (TIMPs) modulation models were developed in Apoe−/− mice in order to determine their contributory role to coronary artery atherosclerosis and associated effect on myocardial fibrosis and remodelling
Summary
A wide range of cardiovascular pathologies including, but not limited to, atherosclerotic plaque progression and rupture, and ensuing adverse post-myocardial infarction (MI) remodelling are highly dependent on extracellular matrix (ECM) turnover[1]. An imbalance between MMP and TIMP levels results in dysregulated proteolytic activity and commonly unfavourable ECM remodelling, and is associated with coronary artery atherosclerotic plaque progression and instability, alongside adverse post-MI fibrosis and subsequent heart failure[2]. With increased apoptosis of macrophage foam cells alongside degradation of the fibrous cap, due to increased MMP activity, coronary atherosclerotic plaques become increasingly prone to rupture, which can trigger occlusive thrombus formation and induce an MI4,6. MMP-7, -9, and -12 and TIMP-1 and TIMP-2 were studied, based on their identified roles in the progression and destabilisation of brachiocephalic plaques within atherosclerotic Apolipoprotein E-deficient ( Apoe−/−) mice[5,12,13] For this purpose, chronic hypercholesterolaemic A poe−/− mice were used and the effect of specific MMP/TIMP modulations was investigated in regard to occurrence of sudden death, coronary artery atherosclerosis, cardiac fibrosis, and remodelling
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