Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
Department of Spinal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
Toxicol Appl Pharmacol. 2021 Sep 15;427:115654. doi: 10.1016/j.taap.2021.115654. Epub 2021 Jul 23.
Diabetic cardiomyopathy (DCM) is a serious diabetic complication that lacks effective preventive or therapeutic approaches. Wild-type and Klf15 knockout (Klf15-KO) mice were fed with either high fat diet (HFD, 60% kcal from fat) or normal diet (ND, 10% kcal from fat) for 3 months and then injected with streptozotocin or vehicle, to induce type 2 diabetes (T2D). All T2D and age-matched control mice were treated with or without SDF-1β at 5 mg/kg body-weight twice a week and also continually received HFD or ND for 3 months. At the end of 6-month study, after cardiac functions were measured, mice were euthanized to collect heart tissue. For in vitro mechanistic study, H9c2 cells were exposed to palmitate to mimic in vivo condition of T2D. SDF-1β prevented T2D-induced cardiac dysfunction and fibrosis and T2D-down-regulated KLF15 expression in wild-type diabetic heart tissue. However, the preventive effects of SDF-1β on both KLF15 expression and fibrosis was abolished, with partial cardiac protection in Klf15-KO/T2D mice. These results demonstrate partial KLF15-dependence for SDF-1β's cardiac fibrotic protection from T2D, but not on SDF-1β's protective effects on T2D-induced cardiac dysfunction. Further study showed that SDF-1β inhibited palmitate-induced cardiomyocyte fibrosis through its receptor CXCR7-mediated activation of p38β MAPK signaling pathway.
糖尿病心肌病（DCM）是一种严重的糖尿病并发症，缺乏有效的预防或治疗方法。野生型和 Klf15 敲除（Klf15-KO）小鼠分别用高脂肪饮食（HFD，60%的热量来自脂肪）或正常饮食（ND，10%的热量来自脂肪）喂养 3 个月，然后用链脲佐菌素或载体注射，以诱导 2 型糖尿病（T2D）。所有 T2D 和年龄匹配的对照小鼠均用或不用 SDF-1β（5mg/kg 体重，每周 2 次）治疗，并继续接受 HFD 或 ND 喂养 3 个月。在 6 个月的研究结束时，测量心功能后，处死小鼠收集心脏组织。对于体外机制研究，将 H9c2 细胞暴露于棕榈酸中以模拟体内 T2D 条件。SDF-1β可预防 T2D 诱导的心脏功能障碍和纤维化，并下调野生型糖尿病心脏组织中的 KLF15 表达。然而，SDF-1β 对 KLF15 表达和纤维化的预防作用被废除，在 Klf15-KO/T2D 小鼠中部分保留了心脏保护作用。这些结果表明，SDF-1β 对 T2D 诱导的心脏纤维化的保护作用部分依赖于 KLF15，但对 SDF-1β 对 T2D 诱导的心脏功能障碍的保护作用不依赖于 KLF15。进一步的研究表明，SDF-1β 通过其受体 CXCR7 介导的 p38β MAPK 信号通路的激活抑制棕榈酸诱导的心肌细胞纤维化。
