Department of Pharmacology, Guangzhou Medical University, Guangzhou 510182, PR China.
Cardiovasc Res. 2012 Sep 1;95(4):507-16. doi: 10.1093/cvr/cvs216. Epub 2012 Jun 28.
The incidence and mortality of myocardial infarction (MI) in diabetic patients are higher than in non-diabetic patients; however, the mechanisms by which diabetes results in cardiac dysfunction are poorly understood. The present study tested the hypothesis that an impaired sonic hedgehog (Shh) pathway contributes to cardiac dysfunction in type 1 diabetic mice with MI.
Adult male C57/B6 mice and streptozotocin-induced type 1 diabetic mice were used. Myocardial proteins of Shh, Patched-1 (Ptc1), and glioma-associated oncogene-1 (Gli1) were significantly decreased in type 1 diabetic mice at 10 weeks, and this was accompanied by cardiac dysfunction. Although myocardial proteins of Shh, Ptc1, and Gli1 were significantly increased 7 days after MI compared with the sham group in control mice, these proteins were markedly decreased in streptozotocin-induced diabetic mice. Treatment with Shh pathway agonist for 21 days significantly increased Ptc1 and Gli1 proteins, enhanced capillary density, reduced the percentage myocardial infarct, and then improved cardiac function in diabetic mice with MI compared with those with no drug treatment. This treatment had no effects in control mice with MI. Conversely, treatment with Shh pathway antagonist for 21 days significantly decreased Ptc1 and Gli1 proteins, reduced capillary density, enlarged the percentage myocardial infarct, and then exacerbated cardiac dysfunction in control mice with MI compared with those with no drug treatment.
These findings indicate that in type 1 diabetic mice the myocardial Shh pathway is impaired and that the impaired Shh pathway contributes to cardiac dysfunction. Strategies that are aimed at augmenting the Shh pathway may offer useful means for improving diabetic cardiac dysfunction.
糖尿病患者心肌梗死（MI）的发病率和死亡率高于非糖尿病患者；然而，糖尿病导致心脏功能障碍的机制尚不清楚。本研究检验了这样一个假设，即受损的 Sonic Hedgehog（Shh）通路导致 1 型糖尿病伴 MI 的小鼠心脏功能障碍。
使用成年雄性 C57/B6 小鼠和链脲佐菌素诱导的 1 型糖尿病小鼠。在 10 周时，1 型糖尿病小鼠的心肌 Shh、Patched-1（Ptc1）和神经胶质瘤相关癌基因-1（Gli1）蛋白明显减少，同时伴有心脏功能障碍。尽管与对照组的假手术组相比，对照组小鼠 MI 后 7 天心肌 Shh、Ptc1 和 Gli1 蛋白明显增加，但在链脲佐菌素诱导的糖尿病小鼠中这些蛋白明显减少。用 Shh 通路激动剂治疗 21 天可显著增加 Ptc1 和 Gli1 蛋白，增加毛细血管密度，减少心肌梗死百分比，从而改善糖尿病伴 MI 小鼠的心脏功能，与未用药物治疗的小鼠相比。这种治疗对伴有 MI 的对照组小鼠没有影响。相反，用 Shh 通路拮抗剂治疗 21 天可显著降低 Ptc1 和 Gli1 蛋白，减少毛细血管密度，增加心肌梗死百分比，从而加剧对照组伴 MI 小鼠的心脏功能障碍，与未用药物治疗的小鼠相比。
这些发现表明，在 1 型糖尿病小鼠中，心肌 Shh 通路受损，受损的 Shh 通路导致心脏功能障碍。增强 Shh 通路的策略可能为改善糖尿病性心脏功能障碍提供有用的手段。
