Churchill Eric, Budas Grant, Vallentin Alice, Koyanagi Tomoyoshi, Mochly-Rosen Daria
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305-5174, USA.
Annu Rev Pharmacol Toxicol. 2008;48:569-99. doi: 10.1146/annurev.pharmtox.48.121806.154902.
Cardiovascular disease is the leading cause of death in the United States. Therefore, identifying therapeutic targets is a major focus of current research. Protein kinase C (PKC), a family of serine/threonine kinases, has been identified as playing a role in many of the pathologies of heart disease. However, the lack of specific PKC regulators and the ubiquitous expression and normal physiological functions of the 11 PKC isozymes has made drug development a challenge. Here we discuss the validity of therapeutically targeting PKC, an intracellular signaling enzyme. We describe PKC structure, function, and distribution in the healthy and diseased heart, as well as the development of rationally designed isozyme-selective regulators of PKC functions. The review focuses on the roles of specific PKC isozymes in atherosclerosis, fibrosis, and cardiac hypertrophy, and examines principles of pharmacology as they pertain to regulators of signaling cascades associated with these diseases.
心血管疾病是美国的主要死因。因此，确定治疗靶点是当前研究的主要重点。蛋白激酶C（PKC）是一类丝氨酸/苏氨酸激酶，已被确定在许多心脏病的病理过程中发挥作用。然而，缺乏特异性PKC调节剂以及11种PKC同工酶的广泛表达和正常生理功能使得药物开发成为一项挑战。在此，我们讨论将细胞内信号酶PKC作为治疗靶点的合理性。我们描述了PKC在健康和患病心脏中的结构、功能和分布，以及合理设计的PKC功能同工酶选择性调节剂的开发。本综述重点关注特定PKC同工酶在动脉粥样硬化、纤维化和心脏肥大中的作用，并探讨与这些疾病相关的信号级联调节剂相关的药理学原理。
