Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.).
Cardiovascular Translational Research Center, University of South Carolina School of Medicine and the WJB Dorn Veteran Affairs Medical Center, Columbia, South Carolina (D.C.L., H.D., G.L.B., E.R., J.A.S., P.D.F., K.N.Z., L.A.F., F.G.S.) and Amgen, Metabolic Disorders, South San Francisco, California (J.W.O., S.S., A.Y.K., T.L.)
J Pharmacol Exp Ther. 2020 Nov;375(2):296-307. doi: 10.1124/jpet.120.000047. Epub 2020 Sep 21.
Infarct expansion can occur after myocardial infarction (MI), which leads to adverse left ventricular (LV) remodeling and failure. An imbalance between matrix metalloproteinase (MMP) induction and tissue inhibitors of MMPs (TIMPs) can accelerate this process. Past studies have shown different biologic effects of TIMP-3, which may depend upon specific domains within the TIMP-3 molecule. This study tested the hypothesis that differential effects of direct myocardial injections of either a full-length recombinant TIMP-3 (F-TIMP-3) or a truncated form encompassing the N-terminal region (N-TIMP-3) could be identified post-MI. MI was induced in pigs that were randomized for MI injections (30 mg) and received targeted injections within the MI region of F-TIMP-3 ( = 8), N-TIMP-3 ( = 9), or saline injection (MI-only, = 11). At 14 days post-MI, LV ejection fraction fell post-MI but remained higher in both TIMP-3 groups. Tumor necrosis factor and interleukin-10 mRNA increased by over 10-fold in the MI-only and N-TIMP-3 groups but were reduced with F-TIMP-3 at this post-MI time point. Direct MI injection of either a full-length or truncated form of TIMP-3 is sufficient to favorably alter the course of post-MI remodeling. The functional and differential relevance of TIMP-3 domains has been established in vivo since the TIMP-3 constructs demonstrated different MMP/cytokine expression profiles. These translational studies identify a unique and more specific therapeutic strategy to alter the course of LV remodeling and dysfunction after MI. SIGNIFICANCE STATEMENT: Using different formulations of tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), when injected into the myocardial infarction (MI) region, slowed the progression of indices of left ventricular (LV) failure, suggesting that the N terminus of TIMP-3 is sufficient to attenuate early adverse functional events post-MI. Injections of full-length recombinant TIMP-3, but not of the N-terminal region of TIMP-3, reduced relative indices of inflammation at the mRNA level, suggesting that the C-terminal region affects other biological pathways. These unique proof-of-concept studies demonstrate the feasibility of using recombinant small molecules to selectively interrupt adverse LV remodeling post-MI.
梗塞扩张可能发生在心肌梗死 (MI) 之后，这会导致左心室 (LV) 不良重塑和衰竭。基质金属蛋白酶 (MMP) 诱导与基质金属蛋白酶抑制剂 (TIMP) 之间的不平衡会加速这一过程。过去的研究表明 TIMP-3 具有不同的生物学效应，这可能取决于 TIMP-3 分子中的特定结构域。本研究检验了这样一个假设，即在 MI 后可以确定直接心肌注射全长重组 TIMP-3 (F-TIMP-3) 或包含 N 端区域的截断形式 (N-TIMP-3) 的差异效应。将 MI 诱导到猪中，随机进行 MI 注射 (30mg)，并在 MI 区域内进行靶向注射，F-TIMP-3 ( = 8)、N-TIMP-3 ( = 9) 或生理盐水注射 (仅 MI， = 11)。在 MI 后 14 天，LV 射血分数在 MI 后下降，但在 TIMP-3 两组中仍较高。肿瘤坏死因子和白细胞介素-10 mRNA 在仅 MI 和 N-TIMP-3 组中增加了 10 倍以上，但在此时点用 F-TIMP-3 降低。直接 MI 注射全长或截断形式的 TIMP-3 足以有利地改变 MI 后重塑的过程。TIMP-3 结构域的功能和差异相关性已在体内得到确立，因为 TIMP-3 构建体表现出不同的 MMP/细胞因子表达谱。这些转化研究确定了一种独特且更具特异性的治疗策略，可改变 MI 后 LV 重塑和功能障碍的进程。意义陈述：使用组织抑制剂基质金属蛋白酶-3 (TIMP-3) 的不同配方，当注射到心肌梗死 (MI) 区域时，会减缓左心室 (LV) 衰竭指数的进展，表明 TIMP-3 的 N 端足以减轻 MI 后早期的不良功能事件。全长重组 TIMP-3 的注射，但不是 TIMP-3 的 N 端区域的注射，在 mRNA 水平上降低了相对炎症指数，表明 C 端区域影响其他生物学途径。这些独特的概念验证研究表明，使用重组小分子选择性中断 MI 后不良的 LV 重塑是可行的。
