吡格列酮通过增强脂联素表达和调节巨噬细胞表型增强脂肪来源的再生细胞对缺血性心肌病的治疗效果。

BACKGROUND: The efficacy of cell transplantation in heart failure is reportedly modest, but adjuvant drugs combined with cell therapy may improve this efficacy. Peroxisome proliferator-activated receptor (PPAR)γ, one of the hypoglycemic medicine for diabetes mellitus, reportedly enhances cytokine production in adipose tissue-derived regenerative cells (ADRCs). We hypothesized that combined administration of PPARγ agonists and ADRCs may enhance the paracrine effects of adiponectin (APN), leading to functional recovery in a chronic myocardial infarction (MI) model. METHODS: ADRCs were isolated from adipose tissues of adult rats by gradient centrifugation and embedded in bio-compatible fibrin-glue to produce ADRCs grafts. In the in vitro study, the ADRCs grafts released APN, which was significantly enhanced by the PPARγ agonist (PGZ, pioglitazone). Transplantation of ADRCs grafts (group A), ADRCs mixed with PGZ (group AP), APN knockdown-ADRCs (group Si) or PGZ (group P) onto the epicardium or a sham operation (group C) was performed (n = 10-20 per group). RESULTS: The AP group showed significant improvement in ejection fraction compared to that in the other groups. In the AP group, a significantly larger number of M2-polarized macrophages was detected and existed for a significantly longer duration in the infarct area. Furthermore, comparing Si group and P group, western blotting of T-cadherin revealed that exogenous APN and local expression of T-cadherin were essential to this histological change and recovery of cardiac function. CONCLUSIONS: Combined administration of PPARγ agonist and ADRSCs activated M2-polarized macrophages with enhancement of APN paracrine effects and lead to better cardiac function in a rat infarction model.

背景：据报道，细胞移植治疗心力衰竭的疗效有限，但辅助药物联合细胞治疗可能会提高这种疗效。过氧化物酶体增殖物激活受体（PPAR）γ是一种用于治疗糖尿病的降血糖药物，据报道可增强脂肪组织来源的再生细胞（ADRCs）中的细胞因子产生。我们假设联合使用 PPARγ 激动剂和 ADRCs 可能会增强脂联素（APN）的旁分泌作用，从而导致慢性心肌梗死（MI）模型中的功能恢复。

方法：通过梯度离心从成年大鼠的脂肪组织中分离出 ADRCs，并将其嵌入生物相容的纤维蛋白胶中以产生 ADRCs 移植物。在体外研究中，ADRCs 移植物释放 APN，PPARγ 激动剂（PGZ，吡格列酮）可显著增强 APN 的释放。将 ADRCs 移植物（A 组）、与 PGZ 混合的 ADRCs（AP 组）、ADRCs 敲低-APN（Si 组）或 PGZ（P 组）移植到心外膜或假手术（C 组）（每组 10-20 只）。

结果：与其他组相比，AP 组的射血分数明显改善。在 AP 组中，梗死区检测到更多的 M2 极化的巨噬细胞，且存在时间更长。此外，与 Si 组和 P 组相比，T-钙黏蛋白的 Western blot 分析表明，外源性 APN 和局部表达 T-钙黏蛋白对这种组织学变化和心脏功能的恢复至关重要。

结论：联合使用 PPARγ 激动剂和 ADRSCs 可激活 M2 极化的巨噬细胞，增强 APN 的旁分泌作用，从而改善大鼠梗死模型中的心脏功能。