Journal
JOURNAL OF PHARMACOLOGICAL SCIENCES
Volume 121, Issue 3, Pages 177-184Publisher
JAPANESE PHARMACOLOGICAL SOC
DOI: 10.1254/jphs.12R13CP
Keywords
cardiovascular disease; SSRI; hypertrophy; sigma-1 receptor; endothelial NOS
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [Kakenhi 22390109]
- Grants-in-Aid for Scientific Research [24659024] Funding Source: KAKEN
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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.
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