Abstract 301: Bone Marrow Niche-Mediates Cardiac Repair is Associated With Adiponectin in Retnla Deficiency

Abstract

Background: Resistin like α (Retnla) is known to be upregulated in anti-inflammatory macrophages and to modulate lipid profile in atherosclerosis. However, the role of Retnla is unknown in the cardiac pathology. Methods: Myocardial infarction (MI) was induced in wild type, Retnla knockout (KO), and Retnla transgenic (TG) mice. Cardiomyocytes, cardiac fibroblasts, macrophages and bone marrow cells were treated with Retnla protein for mechanistic studies. For an adoptive transfer, bone marrow cells were isolated from KO mice to transplant to the infarcted heart. Results: TUNEL staining showed the number of apoptotic cardiomyocytes was higher in the Retnla KO mice than in the TG mice 1 day after MI. Cardiac function and angiogenesis were significantly better in the Retnla KO group, while were worsen in the TG group. Retnla is an anti-inflammatory marker in macrophages, but the expressions of inflammation-related genes were not different between both groups. Interestingly, however, the numbers of macrophages isolated from bone marrow, peritoneum, and cardiac tissue of Retnla KO mice were higher than in the wild type mice. Moreover, phospho-histone H3-positive proliferating cells in the bone marrow were much more abundant in the Retnla KO mice than in the wild type mice. Adiponectin was highly expressed in bone marrow of KO mice, and we transplanted bone marrow cells from KO mice to recipient wild type mice. Two weeks after MI, recipient group transplanted with bone marrow cells from KO mice showed better angiogenesis, reserved cardiac function, and more anti-inflammatory macrophages. In Retnla-treated cardiomyocytes, bax, phopho-p38, and p21 were notably upregulated, while bcl2 and adiponectin were significantly reduced. To examine whether Retnla acted negatively on adiponectin, we administrated a synthetic adiponectin receptor agonist AdipoRon to Retnla-treated cardiomyocytes. AdipoRon blunted the effect of Retnla on cardiomyocytes. These data showed better cardiac recovery was associated with bone marrow-derived adiponectin in the Retnla KO group. Conclusion: Our study suggested that substantial cardiac recovery was strongly associated with adiponectin derived from highly proliferating bone marrow cells in Retnla KO mice.