Ruiz Matthieu, Coderre Lise, Lachance Dominic, Houde Valérie, Martel Cécile, Thompson Legault Julie, Gillis Marc-Antoine, Bouchard Bertrand, Daneault Caroline, Carpentier André C, Gaestel Matthias, Allen Bruce G, Des Rosiers Christine
Department of Nutrition, Université de Montréal, Montréal, Québec, Canada Research Center, Montreal Heart Institute, Montréal, Québec, Canada.
Department of Nutrition, Université de Montréal, Montréal, Québec, Canada Research Center, Montreal Heart Institute, Montréal, Québec, Canada Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
Diabetes. 2016 Feb;65(2):381-92. doi: 10.2337/db15-0238. Epub 2015 Nov 11.
Heart disease remains a major complication of diabetes, and the identification of new therapeutic targets is essential. This study investigates the role of the protein kinase MK2, a p38 mitogen-activated protein kinase downstream target, in the development of diabetes-induced cardiomyopathy. Diabetes was induced in control (MK2(+/+)) and MK2-null (MK2(-/-)) mice using repeated injections of a low dose of streptozotocin (STZ). This protocol generated in MK2(+/+) mice a model of diabetes characterized by a 50% decrease in plasma insulin, hyperglycemia, and insulin resistance (IR), as well as major contractile dysfunction, which was associated with alterations in proteins involved in calcium handling. While MK2(-/-)-STZ mice remained hyperglycemic, they showed improved IR and none of the cardiac functional or molecular alterations. Further analyses highlighted marked lipid perturbations in MK2(+/+)-STZ mice, which encompass increased 1) circulating levels of free fatty acid, ketone bodies, and long-chain acylcarnitines and 2) cardiac triglyceride accumulation and ex vivo palmitate β-oxidation. MK2(-/-)-STZ mice were also protected against all these diabetes-induced lipid alterations. Our results demonstrate the benefits of MK2 deletion on diabetes-induced cardiac molecular and lipid metabolic changes, as well as contractile dysfunction. As a result, MK2 represents a new potential therapeutic target to prevent diabetes-induced cardiac dysfunction.
心脏病仍然是糖尿病的主要并发症，确定新的治疗靶点至关重要。本研究调查了蛋白激酶MK2（一种p38丝裂原活化蛋白激酶的下游靶点）在糖尿病性心肌病发展中的作用。使用低剂量链脲佐菌素（STZ）反复注射，在对照（MK2(+/+)）小鼠和MK2基因敲除（MK2(-/-)）小鼠中诱导糖尿病。该方案在MK2(+/+)小鼠中产生了一种糖尿病模型，其特征为血浆胰岛素降低50%、高血糖和胰岛素抵抗（IR），以及主要的收缩功能障碍，这与钙处理相关蛋白的改变有关。虽然MK2(-/-)-STZ小鼠仍为高血糖，但它们的IR得到改善，且未出现任何心脏功能或分子改变。进一步分析突出显示了MK2(+/+)-STZ小鼠中明显的脂质紊乱，包括1）游离脂肪酸、酮体和长链酰基肉碱的循环水平升高，以及2）心脏甘油三酯积累和离体棕榈酸β氧化增加。MK2(-/-)-STZ小鼠也免受所有这些糖尿病诱导的脂质改变的影响。我们的结果证明了敲除MK2对糖尿病诱导的心脏分子和脂质代谢变化以及收缩功能障碍的益处。因此，MK2是预防糖尿病性心脏功能障碍的一个新的潜在治疗靶点。
