Laboratory of Cardiovascular Pathology, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, England, UK.
Sci Rep. 2021 Nov 30;11(1):23081. doi: 10.1038/s41598-021-02508-4.
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.
基质金属蛋白酶（MMP）的活性受到内源性组织抑制剂（TIMPs）的严格调节，而活性失调会导致细胞外基质重塑。因此，MMP/TIMP 平衡与动脉粥样硬化斑块的进展和不稳定性有关，以及梗死后心脏纤维化和随后心力衰竭的不良后果。在这里，我们证明了长时间高脂肪喂养载脂蛋白（Apo）E 缺陷小鼠会引发不稳定的冠状动脉粥样硬化，同时伴有心肌梗死和进行性猝死的证据。因此，在 36 周高脂肪喂养后，通过同时缺失 Mmp7、Mmp9、Mmp12 或 Timp1 以及相关的野生型对照，研究了 MMP 和 TIMP 对这两种相关疾病进展的选择作用。Mmp7 缺失增加了猝死的发生率，而 Mmp12 缺失促进了生存，而 Mmp9 或 Timp1 缺失则没有影响。虽然所有小鼠都存在冠状动脉疾病，但与相关对照相比，Mmp7 缺陷和 Mmp12 缺陷小鼠的动脉粥样硬化负担减少，而 Timp1 缺陷动物的动脉粥样硬化负担增加。只有在 Mmp-7 缺陷和 Timp1 缺陷动物中观察到心脏纤维化有显著差异，这与毛细血管数量减少有关。在 Apoe 缺陷小鼠中采用治疗策略，TIMP-2 腺病毒过表达或非选择性 MMP 抑制剂（RS-130830）的给药（延迟或贯穿）对冠状动脉粥样硬化负担或心脏纤维化没有影响。总之，我们的研究结果强调了 MMP 在冠状动脉斑块进展和相关梗死后心脏纤维化中的不同作用，突出了需要针对不稳定的动脉粥样硬化以及不良的心脏重塑采取有针对性的治疗方法，同时消除对任何一种病理的不利的不良影响，针对 MMP-12 似乎是一个合适的靶点。
