Division of Molecular Cardiovascular Biology, Department of Pediatrics, The Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
J Pharmacol Sci. 2013;121(3):177-84. doi: 10.1254/jphs.12r13cp. Epub 2013 Feb 22.
Depression is associated with a substantial increase in the risk of developing heart failure and is independently associated with increased cardiovascular morbidity and mortality. Inversely, cardiovascular disease can lead to severe depression. Thus, therapy with selective serotonin reuptake inhibitors (SSRIs) is strongly recommended to reduce cardiovascular disease-induced morbidity and mortality. However, molecular mechanisms to support evidence-based SSRI treatment of cardiovascular disease have not been elucidated. We recently found very high expression of the sigma-1 receptor, an orphan receptor, in rat heart tissue and defined the cardiac sigma-1 receptor as a direct SSRI target in eliciting cardioprotection in both pressure overload (PO)induced and transverse aortic constriction (TAC)-induced myocardial hypertrophy models in rodents. Our findings suggest that SSRIs such as fluvoxamine protect against PO- and TAC-induced cardiac dysfunction by upregulating sigma-1 receptor expression and stimulating sigma-1 receptor-mediated Akt-eNOS signaling. Here, we discuss the association of depression and cardiovascular diseases, the protective mechanism of SSRIs in heart failure patients, and the pathophysiological relevance of sigma-1 receptors to progression of heart failure. These findings should promote development of clinical therapeutics targeting the sigma-1 receptor in cardiovascular diseases.
抑郁症与心力衰竭风险显著增加相关，且独立于其他因素增加心血管发病率和死亡率。相反，心血管疾病可导致严重的抑郁症。因此，强烈推荐使用选择性 5-羟色胺再摄取抑制剂（SSRIs）进行治疗，以降低心血管疾病引起的发病率和死亡率。然而，支持基于循证的 SSRI 治疗心血管疾病的分子机制尚未阐明。我们最近发现，大鼠心脏组织中存在很高水平的 sigma-1 受体表达，sigma-1 受体是一种孤儿受体，在压力超负荷（PO）诱导和横主动脉缩窄（TAC）诱导的啮齿动物心肌肥厚模型中，将心脏 sigma-1 受体定义为直接的 SSRI 靶标，可引发心脏保护作用。我们的研究结果表明，氟伏沙明等 SSRIs 通过上调 sigma-1 受体表达和刺激 sigma-1 受体介导的 Akt-eNOS 信号通路来预防 PO 和 TAC 诱导的心脏功能障碍。在这里，我们讨论了抑郁症与心血管疾病的关联、SSRIs 在心力衰竭患者中的保护机制，以及 sigma-1 受体在心力衰竭进展中的病理生理学相关性。这些发现应该会促进针对心血管疾病中 sigma-1 受体的临床治疗方法的发展。
