Prince Henry's Institute of Medical Research, Clayton, VIC 3168, Australia.
Clin Sci (Lond). 2013 Nov;125(9):409-21. doi: 10.1042/CS20130050.
MR (mineralocorticoid receptor) activation in the heart plays a central role in the development of cardiovascular disease, including heart failure. The MR is present in many cell types within the myocardium, including cardiomyocytes, macrophages and the coronary vasculature. The specific role of the MR in each of these cell types in the initiation and progression of cardiac pathophysiology is not fully understood. Cardiomyocyte MRs are increasingly recognized to play a role in regulating cardiac function, electrical conduction and fibrosis, through direct signal mediation and through paracrine MR-dependent activity. Although MR blockade in the heart is an attractive therapeutic option for the treatment of heart failure and other forms of heart disease, current antagonists are limited by side effects owing to MR inactivation in other tissues (including renal targets). This has led to increased efforts to develop therapeutics that are more selective for cardiac MRs and which may have reduced the occurrence of side effects in non-cardiac tissues. A major clinical consideration in the treatment of cardiovascular disease is of the differences between males and females in the incidence and outcomes of cardiac events. There is clinical evidence that female sensitivity to endogenous MRs is more pronounced, and experimentally that MR-targeted interventions may be more efficacious in females. Given that sex differences have been described in MR signalling in a range of experimental settings and that the MR and oestrogen receptor pathways share some common signalling intermediates, it is becoming increasingly apparent that the mechanisms of MRs need to be evaluated in a sex-selective manner. Further research targeted to identify sex differences in cardiomyocyte MR activation and signalling processes has the potential to provide the basis for the development of cardiac-specific MR therapies that may also be sex-specific.
心脏中的 MR（盐皮质激素受体）激活在心血管疾病的发展中起着核心作用，包括心力衰竭。MR 存在于心肌中的许多细胞类型中，包括心肌细胞、巨噬细胞和冠状动脉血管。MR 在这些细胞类型中的每一种在心脏病理生理学的起始和进展中的具体作用尚未完全了解。越来越多的人认识到心肌细胞 MR 通过直接信号转导和旁分泌 MR 依赖性活性在调节心脏功能、电传导和纤维化方面发挥作用。尽管心脏中的 MR 阻断是治疗心力衰竭和其他形式心脏病的一种有吸引力的治疗选择，但由于其他组织（包括肾脏靶标）中 MR 失活，当前的拮抗剂受到副作用的限制。这导致人们越来越努力开发对心脏 MR 更具选择性的治疗方法，这些方法可能会减少非心脏组织中副作用的发生。在心血管疾病治疗中一个主要的临床考虑因素是心脏事件在男性和女性中的发生率和结果之间的差异。有临床证据表明，女性对内源性 MR 的敏感性更为明显，而且实验表明，针对 MR 的干预措施在女性中可能更有效。鉴于在多种实验环境中已经描述了 MR 信号转导的性别差异，并且 MR 和雌激素受体途径共享一些共同的信号转导中间物，越来越明显的是，MR 的机制需要以性别选择性的方式进行评估。进一步针对鉴定心肌细胞 MR 激活和信号转导过程中的性别差异的研究有可能为开发可能具有性别特异性的心脏特异性 MR 治疗方法提供基础。
