Department of Nutrition, Université de Montréal, Montreal, Quebec, Canada; Montreal Heart Institute, Research Center, 5000 Belanger Street, Montreal, Quebec, Canada.
Department of Nutrition, Université de Montréal, Montreal, Quebec, Canada; Department of Medicine, Université de Montréal, Montreal, Quebec, Canada; Montreal Heart Institute, Research Center, 5000 Belanger Street, Montreal, Quebec, Canada.
Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt B):1914-1922. doi: 10.1016/j.bbadis.2017.07.015. Epub 2017 Jul 19.
Various signaling pathways have been identified in the heart as important players during development, physiological adaptation or pathological processes. This includes the MAPK families, particularly p38MAPK, which is involved in several key cellular processes, including differentiation, proliferation, apoptosis, inflammation, metabolism and survival. Disrupted p38MAPK signaling has been associated with several diseases, including cardiovascular diseases (CVD) as well as diabetes and its related complications. Despite efforts to translate this knowledge into therapeutic avenues, p38 inhibitors have failed in clinical trials due to adverse effects. Inhibition of MK2, a downstream target of p38, appears to be a promising alternative strategy. Targeting MK2 activity may avoid the adverse effects linked to p38 inhibition, while maintaining its beneficial effects. MK2 was first considered as a therapeutic target in inflammatory diseases such as rheumatoid polyarthritis. A growing body of evidence now supports a key role of MK2 signaling in the pathogenesis of CVD, particularly ischemia/reperfusion injury, hypertrophy, and hypertension and that its inhibition or inactivation is associated with improved heart and vascular functions. More recently, MK2 was shown to be a potential player in diabetes and related complications, particularly in liver and heart, and perturbations in calcium handling and lipid metabolism. In this review, we will discuss recent advances in our knowledge of the role of MK2 in p38MAPK-mediated signaling and the benefits of its loss of function in CVD and diabetes, with an emphasis on the roles of MK2 in calcium handling and lipid metabolism. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.
多种信号通路已被鉴定在心脏中作为重要的参与者在发育过程中、生理适应或病理过程。这包括 MAPK 家族，尤其是 p38MAPK，其参与几个关键的细胞过程，包括分化、增殖、凋亡、炎症、代谢和存活。破坏 p38MAPK 信号与几种疾病有关，包括心血管疾病 (CVD) 以及糖尿病及其相关并发症。尽管努力将这些知识转化为治疗途径，p38 抑制剂在临床试验中由于不良反应而失败。抑制 p38 的下游靶点 MK2 似乎是一种有前途的替代策略。靶向 MK2 活性可能避免与 p38 抑制相关的不良反应，同时保持其有益的作用。MK2 最初被认为是一种在炎症性疾病如类风湿关节炎的治疗靶点。越来越多的证据支持 MK2 信号在 CVD 的发病机制中的关键作用，特别是缺血/再灌注损伤、肥大、高血压，其抑制或失活与改善心脏和血管功能有关。最近，MK2 被证明是糖尿病及其相关并发症的一个潜在的参与者，特别是在肝脏和心脏，以及钙处理和脂质代谢的干扰。在这篇综述中，我们将讨论最近在我们的知识进步的角色在 p38MAPK 介导的信号通路和 MK2 功能丧失的好处在 CVD 和糖尿病，强调了 MK2 在钙处理和脂质代谢中的作用。这篇文章是一个特刊的一部分，题为心脏适应肥胖、糖尿病和胰岛素抵抗，由教授 Jan F.C. Glatz，Jason R.B. Dyck 和 Christine Des Rosiers 编辑。
