Mollenhauer Martin, Friedrichs Kai, Lange Max, Gesenberg Jan, Remane Lisa, Kerkenpaß Christina, Krause Jenny, Schneider Johanna, Ravekes Thorben, Maass Martina, Halbach Marcel, Peinkofer Gabriel, Saric Tomo, Mehrkens Dennis, Adam Matti, Deuschl Florian G, Lau Denise, Geertz Birgit, Manchanda Kashish, Eschenhagen Thomas, Kubala Lukas, Rudolph Tanja K, Wu Yuping, Tang W H Wilson, Hazen Stanley L, Baldus Stephan, Klinke Anna, Rudolph Volker
From the Cardiology, Heart Center (M.M., K.F., M.L., J.G., L.R., C.K., J.S., T.R., M.M., M.H., G.P., D.M., M.A., K.M., T.K.R., S.B., A.K., V.R.), Center for Molecular Medicine Cologne (M.M., K.F., M.L., J.G., L.R., C.K., J.S., T.R., M.M., M.H., G.P., D.M., M.A., K.M., T.K.R., S.B., A.K., V.R.), and Center for Physiology and Pathophysiology, Institute for Neurophysiology, Medical Faculty (T.S.), University of Cologne, Germany; University Heart Center Hamburg, Germany (J.K., D.L.); General and Interventional Cardiology (F.G.D.) and Experimental Pharmacology and Toxicology (B.G., T.E.), University Heart Center Hamburg, University Hospital Hamburg-Eppendorf (UKE), Germany; Institute of Biophysics, Czech Academy of Sciences, Brno (L.K.); International Clinical Research Center, St. Anne's University Hospital Brno, Czech Republic (L.K., A.K.); Mathematics, Cleveland State University, OH (Y.W.); and Cellular and Molecular Medicine and Cardiovascular Medicine, Cleveland Clinic, OH (W.H.W.T., S.L.H.).
Circ Res. 2017 Jun 23;121(1):56-70. doi: 10.1161/CIRCRESAHA.117.310870. Epub 2017 Apr 12.
Ventricular arrhythmias remain the leading cause of death in patients suffering myocardial ischemia. Myeloperoxidase, a heme enzyme released by polymorphonuclear neutrophils, accumulates within ischemic myocardium and has been linked to adverse left ventricular remodeling.
To reveal the role of myeloperoxidase for the development of ventricular arrhythmias.
In different murine models of myocardial ischemia, myeloperoxidase deficiency profoundly decreased vulnerability for ventricular tachycardia on programmed right ventricular and burst stimulation and spontaneously as assessed by ECG telemetry after isoproterenol injection. Experiments using CD11b/CD18 integrin-deficient (CD11b) mice and intravenous myeloperoxidase infusion revealed that neutrophil infiltration is a prerequisite for myocardial myeloperoxidase accumulation. Ventricles from myeloperoxidase-deficient (Mpo) mice showed less pronounced slowing and decreased heterogeneity of electric conduction in the peri-infarct zone than wild-type mice. Expression of the redox-sensitive gap junctional protein Cx43 (Connexin 43) was reduced in the peri-infarct area of wild-type compared with Mpo mice. In isolated wild-type cardiomyocytes, Cx43 protein content decreased on myeloperoxidase/HO incubation. Mapping of induced pluripotent stem cell-derived cardiomyocyte networks and in vivo investigations linked Cx43 breakdown to myeloperoxidase-dependent activation of matrix metalloproteinase 7. Moreover, Mpo mice showed decreased ventricular postischemic fibrosis reflecting reduced accumulation of myofibroblasts. Ex vivo, myeloperoxidase was demonstrated to induce fibroblast-to-myofibroblast transdifferentiation by activation of p38 mitogen-activated protein kinases resulting in upregulated collagen generation. In support of our experimental findings, baseline myeloperoxidase plasma levels were independently associated with a history of ventricular arrhythmias, sudden cardiac death, or implantable cardioverter-defibrillator implantation in a cohort of 2622 stable patients with an ejection fraction >35% undergoing elective diagnostic cardiac evaluation.
Myeloperoxidase emerges as a crucial mediator of postischemic myocardial remodeling and may evolve as a novel pharmacological target for secondary disease prevention after myocardial ischemia.
室性心律失常仍然是心肌缺血患者死亡的主要原因。髓过氧化物酶是一种由多形核中性粒细胞释放的血红素酶，在缺血心肌中蓄积，并与左心室不良重塑有关。
揭示髓过氧化物酶在室性心律失常发生发展中的作用。
在不同的心肌缺血小鼠模型中，髓过氧化物酶缺乏显著降低了程序性右心室刺激和爆发刺激时室性心动过速的易感性，以及注射异丙肾上腺素后通过心电图遥测评估的自发性室性心动过速的易感性。使用CD11b/CD18整合素缺陷（CD11b）小鼠和静脉注射髓过氧化物酶的实验表明，中性粒细胞浸润是心肌髓过氧化物酶蓄积的前提条件。与野生型小鼠相比，髓过氧化物酶缺陷（Mpo）小鼠的心室在梗死周边区电传导减慢和不均一性降低的程度较轻。与Mpo小鼠相比，野生型小鼠梗死周边区氧化还原敏感的缝隙连接蛋白Cx43（连接蛋白43）的表达降低。在分离的野生型心肌细胞中，髓过氧化物酶/HO孵育后Cx43蛋白含量降低。对诱导多能干细胞衍生的心肌细胞网络进行标测以及体内研究表明，Cx43降解与髓过氧化物酶依赖性基质金属蛋白酶7的激活有关。此外，Mpo小鼠的心室缺血后纤维化减少，反映成肌纤维细胞蓄积减少。在体外，髓过氧化物酶被证明可通过激活p38丝裂原活化蛋白激酶诱导成纤维细胞向肌成纤维细胞转分化，从而导致胶原蛋白生成上调。支持我们实验结果的是，在2622例射血分数>35%且正在接受择期诊断性心脏评估的稳定患者队列中，基线髓过氧化物酶血浆水平与室性心律失常病史、心源性猝死或植入式心脏复律除颤器植入独立相关。
髓过氧化物酶是缺血后心肌重塑的关键介质，可能成为心肌缺血后二级疾病预防的新型药理学靶点。
