Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center , Jackson, Mississippi.
Department of Geriatric Medicine, University of Oklahoma Health Sciences Center , Oklahoma City, Oklahoma.
Am J Physiol Heart Circ Physiol. 2018 Feb 1;314(2):H224-H235. doi: 10.1152/ajpheart.00453.2017. Epub 2017 Oct 13.
Matrix metalloproteinase (MMP)-9 increases in the myocardium with advanced age and after myocardial infarction (MI). Because young transgenic (TG) mice overexpressing human MMP-9 only in macrophages show better outcomes post-MI, whereas aged TG mice show a worse aging phenotype, we wanted to evaluate the effect of aging superimposed on MI to see if the detrimental effect of aging counteracted the benefits of macrophage MMP-9 overexpression. We used 17- to 28-mo-old male and female C57BL/6J wild-type (WT) and TG mice ( n = 10-21 mice/group) to evaluate the effects of aging superimposed on MI. Despite similar infarct areas and mortality rates at day 7 post-MI, aging TG mice showed improved diastolic properties and remodeling index compared with WT mice (both P < 0.05). Macrophage numbers were higher in TG than WT mice at days 0 and 7 post-MI, and the post-MI increase was due to elevated cluster of differentiation 18 protein levels (all P < 0.05). RNA sequencing analysis of cardiac macrophages isolated from day 7 post-MI infarcts identified 1,276 statistically different (all P < 0.05) genes (994 increased and 282 decreased in TG mice). Reduced expression of vascular endothelial growth factor A, platelet-derived growth factor subunit A, and transforming growth factor-β, along with elevated expression of tissue inhibitor of MMP-4, in macrophages revealed mechanisms of indirect downstream effects on fibroblasts and neovascularization. While collagen accumulation was enhanced in TG mice compared with WT mice at days 0 and 7 post-MI ( P < 0.05 for both), the post-MI collagen cross-linking ratio was higher in WT mice ( P < 0.05), consistent with increased diastolic volumes. Vessel numbers [by Griffonia ( Bandeiraea) simplicifolia lectin I staining] were decreased in TG mice compared with WT mice at days 0 and 7 post-MI ( P < 0.05 for both). In conclusion, macrophage-derived MMP-9 improved post-MI cardiac wound healing through direct and indirect mechanisms to improve diastolic physiology and remodeling. NEW & NOTEWORTHY Aging mice with macrophage overexpression of matrix metalloproteinase-9 have increased macrophage numbers 7 days after myocardial infarction, resulting in improved diastolic physiology and left ventricular remodeling through effects on cardiac wound healing.
基质金属蛋白酶 (MMP)-9 在心肌中随着年龄的增长和心肌梗死 (MI) 而增加。因为年轻的转基因 (TG) 小鼠仅在巨噬细胞中过表达人 MMP-9 后 MI 结局更好，而老年 TG 小鼠表现出更差的衰老表型，所以我们想评估 MI 叠加老化的影响，看看老化的不利影响是否抵消了巨噬细胞 MMP-9 过表达的益处。我们使用 17 至 28 个月大的雄性和雌性 C57BL/6J 野生型 (WT) 和 TG 小鼠 (每组 n = 10-21 只) 来评估 MI 叠加老化的影响。尽管在 MI 后 7 天的梗死面积和死亡率相似，但与 WT 小鼠相比，老年 TG 小鼠的舒张功能和重塑指数得到改善 (均 P < 0.05)。在 MI 后 0 天和 7 天，TG 小鼠的巨噬细胞数量高于 WT 小鼠，而这种增加是由于 CD18 蛋白水平升高所致 (均 P < 0.05)。从 MI 后 7 天梗死灶分离的心脏巨噬细胞的 RNA 测序分析鉴定出 1276 个统计学上不同的 (均 P < 0.05) 基因 (994 个在 TG 小鼠中增加，282 个在 TG 小鼠中减少)。血管内皮生长因子 A、血小板衍生生长因子亚单位 A 和转化生长因子-β的表达减少，同时基质金属蛋白酶-4 的表达增加，表明对成纤维细胞和新生血管形成的间接下游效应的机制。与 WT 小鼠相比，TG 小鼠在 MI 后 0 天和 7 天的胶原积累增加 (均 P < 0.05)，但 WT 小鼠的 MI 后胶原交联率更高 (P < 0.05)，与舒张容积增加一致。与 WT 小鼠相比，TG 小鼠在 MI 后 0 天和 7 天的血管数量 (用 Griffonia [Bandeiraea] simplicifolia lectin I 染色)减少 (均 P < 0.05)。总之，巨噬细胞源性 MMP-9 通过直接和间接机制改善心肌愈合，改善舒张生理和重塑，从而改善 MI 后心脏愈合。
在 MI 后 7 天，过表达基质金属蛋白酶-9 的巨噬细胞的衰老小鼠中巨噬细胞数量增加，导致通过心脏伤口愈合对舒张生理学和左心室重塑产生积极影响。
