School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
J Cardiovasc Pharmacol. 2010 Apr;55(4):385-90. doi: 10.1097/FJC.0b013e3181d3da24.
Myeloid differentiation factor 88 (MyD88) is an endogenous adaptor protein that coordinates the inflammatory response to agonists of the Toll-like receptor and interleukin-1 receptor families. This particular response is activated following myocardial ischemia and infarction and may represent a viable target for pharmacologic inhibition. The current study tested MyD88 inhibitors in a murine model of nonreperfused acute myocardial infarction (AMI).
AMI was induced by permanent ligation of the left coronary artery. Adult, male, Imprinting Control Region mice were randomized to daily injections with 1 of 2 MyD88 pharmacologic inhibitors (ST2825 25 mg/kg or IMG2005 1 mg/kg), saline, or pretreatment with MyD88-targeted silencing small interfering RNA (siRNA) or scrambled nontargeted siRNA (n = 6 for each group). Echocardiography was performed at baseline and 7 days after surgery to evaluate pathologic cardiac enlargement.
Pharmacologic inhibition of MyD88 with ST2825 or IMG2005) and MyD88-targeted siRNA protected against left ventricular (LV) dilatation (reduced LV end-systolic and LV end-diastolic diameter) and hypertrophy. This protection occurred despite no measurable reduction in infarct size.
Pharmacologic MyD88 inhibition protects against pathologic LV remodeling without altering infarct scar formation. MyD88 may be a viable target for pharmacologic inhibition in AMI.
髓样分化因子 88（MyD88）是一种内源性衔接蛋白，可协调 Toll 样受体和白细胞介素-1 受体家族激动剂引发的炎症反应。这种特定反应在心肌缺血和梗死后被激活，可能代表了药物抑制的一个可行靶点。本研究在非再灌注性急性心肌梗死（AMI）的小鼠模型中测试了 MyD88 抑制剂。
通过永久性结扎左冠状动脉诱导 AMI。成年雄性印迹控制区小鼠被随机分为每天注射 2 种 MyD88 药理学抑制剂（ST2825 25mg/kg 或 IMG2005 1mg/kg）、生理盐水、或 MyD88 靶向沉默小干扰 RNA（siRNA）或非靶向 scrambled siRNA 预处理（每组 6 只）。在手术 7 天后进行超声心动图检查，以评估病理性心脏增大。
ST2825 或 IMG2005 对 MyD88 的药理学抑制）和 MyD88 靶向 siRNA 可防止左心室（LV）扩张（减少 LV 收缩末期和 LV 舒张末期直径）和肥大。这种保护作用的发生与梗死面积无明显减少有关。
MyD88 的药理学抑制可防止病理性 LV 重构，而不改变梗死瘢痕形成。MyD88 可能是 AMI 药物抑制的一个可行靶点。
