Kingery Justin R, Hamid Tariq, Lewis Robert K, Ismahil Mohamed Ameen, Bansal Shyam S, Rokosh Gregg, Townes Tim M, Ildstad Suzanne T, Jones Steven P, Prabhu Sumanth D
Department of Medicine, University of Louisville, Louisville, KY, USA.
Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Basic Res Cardiol. 2017 Mar;112(2):19. doi: 10.1007/s00395-017-0609-2. Epub 2017 Feb 25.
In the failing heart, iNOS is expressed by both macrophages and cardiomyocytes. We hypothesized that inflammatory cell-localized iNOS exacerbates left ventricular (LV) remodeling. Wild-type (WT) C57BL/6 mice underwent total body irradiation and reconstitution with bone marrow from iNOS mice (iNOSc) or WT mice (WTc). Chimeric mice underwent coronary ligation to induce large infarction and ischemic heart failure (HF), or sham surgery. After 28 days, as compared with WTc sham mice, WTc HF mice exhibited significant (p < 0.05) mortality, LV dysfunction, hypertrophy, fibrosis, oxidative/nitrative stress, inflammatory activation, and iNOS upregulation. These mice also exhibited a ~twofold increase in circulating Ly6C pro-inflammatory monocytes, and ~sevenfold higher cardiac M1 macrophages, which were primarily CCR2 cells. In contrast, as compared with WTc HF mice, iNOSc HF mice exhibited significantly improved survival, LV function, hypertrophy, fibrosis, oxidative/nitrative stress, and inflammatory activation, without differences in overall cardiac iNOS expression. Moreover, iNOSc HF mice exhibited lower circulating Ly6C monocytes, and augmented cardiac M2 macrophages, but with greater infiltrating monocyte-derived CCR2 macrophages vs. WTc HF mice. Lastly, upon cell-to-cell contact with naïve cardiomyocytes, peritoneal macrophages from WT HF mice depressed contraction, and augmented cardiomyocyte oxygen free radicals and peroxynitrite. These effects were not observed upon contact with macrophages from iNOS HF mice. We conclude that leukocyte iNOS is obligatory for local and systemic inflammatory activation and cardiac remodeling in ischemic HF. Activated macrophages in HF may directly induce cardiomyocyte contractile dysfunction and oxidant stress upon cell-to-cell contact; this juxtacrine response requires macrophage-localized iNOS.
在衰竭心脏中，诱导型一氧化氮合酶（iNOS）由巨噬细胞和心肌细胞共同表达。我们推测炎症细胞定位的iNOS会加剧左心室（LV）重塑。野生型（WT）C57BL/6小鼠接受全身照射，并用来自iNOS小鼠（iNOSc）或WT小鼠（WTc）的骨髓进行重建。嵌合小鼠接受冠状动脉结扎以诱导大面积梗死和缺血性心力衰竭（HF），或进行假手术。28天后，与WTc假手术小鼠相比，WTc HF小鼠表现出显著（p < 0.05）的死亡率、左心室功能障碍、肥大、纤维化、氧化/硝化应激、炎症激活和iNOS上调。这些小鼠循环中的Ly6C促炎单核细胞增加了约两倍，心脏M1巨噬细胞增加了约七倍，这些巨噬细胞主要是CCR2细胞。相比之下，与WTc HF小鼠相比，iNOSc HF小鼠的存活率、左心室功能、肥大、纤维化、氧化/硝化应激和炎症激活均显著改善，而总体心脏iNOS表达无差异。此外，iNOSc HF小鼠循环中的Ly6C单核细胞较少，心脏M2巨噬细胞增加，但与WTc HF小鼠相比，浸润的单核细胞衍生的CCR2巨噬细胞更多。最后，与未接触过的心肌细胞进行细胞间接触时，WT HF小鼠的腹腔巨噬细胞会抑制收缩，并增加心肌细胞的氧自由基和过氧亚硝酸盐。与iNOS HF小鼠的巨噬细胞接触时未观察到这些效应。我们得出结论，白细胞iNOS是缺血性HF中局部和全身炎症激活及心脏重塑所必需的。HF中活化的巨噬细胞在细胞间接触时可能直接诱导心肌细胞收缩功能障碍和氧化应激；这种旁分泌反应需要巨噬细胞定位的iNOS。
