Kain Vasundhara, Ingle Kevin A, Colas Romain A, Dalli Jesmond, Prabhu Sumanth D, Serhan Charles N, Joshi Medha, Halade Ganesh V
Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, AL, USA.
Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Department of Anesthesiology, Perioperative and Pain Medicine, Boston, MA USA.
J Mol Cell Cardiol. 2015 Jul;84:24-35. doi: 10.1016/j.yjmcc.2015.04.003. Epub 2015 Apr 11.
Unresolved inflammation is a major contributor to the development of heart failure following myocardial infarction (MI). Pro-resolving lipid mediators, such as resolvins (e.g. RvD1), are biosynthesized endogenously. The role of RvD1 in resolving post-MI inflammation has not been elucidated due to its unstable nature. Here, we have tested the role for two forms of RvD1, after incorporation into liposomes (Lipo-RvD1) and its free acid form (RvD1) in the left ventricle (LV) and splenic remodeling post-MI. 8 to 12-week old male, C57BL/6J-mice were subjected to coronary artery ligation and Lipo-RvD1 or RvD1 (3 μg/kg/day) was injected 3h post-MI for day (d)1 or until d5. No-MI mice and saline-injected MI mice served as controls. RvD1 injected groups showed improved fractional shortening post-MI; preserving transient changes in the splenic reservoir compared to MI-saline. RvD1-groups showed an early exit of neutrophils from LV and spleen at d5 post-MI with an increased expression of lipoxin A4 receptor (ALX; synonym formyl peptide receptor; FPR2) compared to the MI-saline group. The levels of pro-resolving mediators RvD1, RvD2, Maresin 1 (MaR1) and Lipoxin A4 (LXA4) were increased in spleens from RvD1 injected mice at d5 post-MI. RvD1 administration reduced macrophage density, ccr5 and cxcl5 levels at d5 post-MI compared to saline injected mice (both, p < 0.05). Increased transcripts of mrc-1, arg-1 and Ym-1 (all, p < 0.05) suggest macrophage-mediated clearance of necrotic cells in RvD1-groups. RvD1 reduced the pro-fibrotic genes (colla1, coll2a1 and tnc (all; p < 0.05)) and decreased collagen deposition, thereby reducing post-MI fibrosis and thus stabilizing the extracellular matrix. In summary, RvD1 and Lipo-RvD1 promote the resolution of acute inflammation initiated by MI, thereby delaying the onset of heart failure.
未解决的炎症是心肌梗死（MI）后心力衰竭发展的主要促成因素。促消退脂质介质，如消退素（如RvD1），是内源性生物合成的。由于其性质不稳定，RvD1在解决MI后炎症中的作用尚未阐明。在此，我们测试了两种形式的RvD1在MI后左心室（LV）和脾脏重塑中的作用，一种是掺入脂质体后的形式（脂质体-RvD1），另一种是其游离酸形式（RvD1）。8至12周龄的雄性C57BL/6J小鼠接受冠状动脉结扎，在MI后3小时注射脂质体-RvD1或RvD1（3μg/kg/天），持续1天（d）1或直至d5。未发生MI的小鼠和注射生理盐水的MI小鼠作为对照。注射RvD1的组在MI后显示出缩短分数改善；与MI-生理盐水组相比，脾脏储备的短暂变化得以保留。RvD1组在MI后第5天显示中性粒细胞从LV和脾脏早期退出，与MI-生理盐水组相比，脂氧素A4受体（ALX；同义词甲酰肽受体；FPR2）表达增加。在MI后第5天，注射RvD1的小鼠脾脏中促消退介质RvD1、RvD2、maresin 1（MaR1）和脂氧素A4（LXA4）的水平升高。与注射生理盐水的小鼠相比，在MI后第5天给予RvD1可降低巨噬细胞密度、ccr5和cxcl5水平（两者均p<0.05）。mrc-1、arg-1和Ym-1的转录本增加（均p<0.05）表明RvD1组中巨噬细胞介导的坏死细胞清除。RvD1降低了促纤维化基因（colla1、coll2a1和tnc（均p<0.05））并减少了胶原蛋白沉积，从而减少了MI后的纤维化，进而稳定了细胞外基质。总之，RvD1和脂质体-RvD1促进了由MI引发的急性炎症的消退，从而延迟了心力衰竭的发作。
