Crosstalk between mitogen-activated protein kinases and mitochondria in cardiac diseases: therapeutic perspectives.
Crosstalk between mitogen-activated protein kinases and mitochondria in cardiac diseases: therapeutic perspectives.
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DOI：
10.1016/j.pharmthera.2014.05.013
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发表时间：
2014-11
影响因子：
13.5
通讯作者：
Agostini, Bryan
中科院分区：
文献类型：
--
作者：
Javadov, Sabzali;Jang, Sehwan;Agostini, Bryan
心血管疾病在全世界造成的死亡率和发病率高于任何其他疾病。尽管许多细胞内信号通路影响心脏生理和病理，但丝裂原活化蛋白激酶（MAPK）家族由于其在信号传导和与其他信号传导网络的串扰中的巨大影响而获得了显著的关注。广泛研究的MAPKs ERK 1/2、p38、JNK和ERK 5表现出独特的细胞内信号传导机制，响应于无数的有丝分裂原和应激源，并影响心脏发育、代谢、性能和发病机制的信号传导。尽管30年来对各种动物/细胞模型、应激严重程度和刺激类型进行了广泛的临床研究和基础研究，但MAPK信号传导与心功能不全之间的关系仍然难以捉摸。尽管如此，一些研究已经证明了MAPK与线粒体的相互作用的重要性，线粒体是细胞的动力，为正常的心肌细胞功能提供超过80%的ATP，并在细胞死亡中起着至关重要的作用。虽然许多问题仍然没有答案，但有足够的证据可以考虑靶向MAPK-线粒体相互作用预防和治疗心脏病的可能性。这篇综述的目的是将以前的研究整合到心脏疾病，如心肌梗死（缺血），心肌肥厚和心力衰竭的MAPK和MAPK-线粒体信号转导的讨论中。全面了解相关的分子机制，以及在这一领域的研究面临的挑战，将有助于开发新的药物和基因操作治疗心血管疾病。
Cardiovascular diseases cause more mortality and morbidity worldwide than any other diseases. Although many intracellular signaling pathways influence cardiac physiology and pathology, the mitogen-activated protein kinase (MAPK) family has garnered significant attention because of its vast implications in signaling and cross-talk with other signaling networks. The extensively studied MAPKs ERK1/2, p38, JNK, and ERK5, demonstrate unique intracellular signaling mechanisms, responding to a myriad of mitogens and stressors and influencing the signaling of cardiac development, metabolism, performance, and pathogenesis. Definitive relationships between MAPK signaling and cardiac dysfunction remain elusive, despite 30 years of extensive clinical studies and basic research of various animal/cell models, severities of stress, and types of stimuli. Still, several studies have proven the importance of MAPK cross-talk with mitochondria, powerhouses of the cell that provide over 80% of ATP for normal cardiomyocyte function and play a crucial role in cell death. Although many questions remain unanswered, there exists enough evidence to consider the possibility of targeting MAPK-mitochondria interactions in the prevention and treatment of heart disease. The goal of this review is to integrate previous studies into a discussion of MAPKs and MAPK-mitochondria signaling in cardiac diseases, such as myocardial infarction (ischemia), hypertrophy and heart failure. A comprehensive understanding of relevant molecular mechanisms, as well as challenges for studies in this area, will facilitate the development of new pharmacological agents and genetic manipulations for therapy of cardiovascular diseases.
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