Stimulation of σ1-receptor restores abnormal mitochondrial Ca²⁺ mobilization and ATP production following cardiac hypertrophy.

BACKGROUND

We previously reported that the σ1-receptor (σ1R) is down-regulated following cardiac hypertrophy and dysfunction in transverse aortic constriction (TAC) mice. Here we address how σ1R stimulation with the selective σ1R agonist SA4503 restores hypertrophy-induced cardiac dysfunction through σ1R localized in the sarcoplasmic reticulum (SR).

METHODS

We first confirmed anti-hypertrophic effects of SA4503 (0.1-1μM) in cultured cardiomyocytes exposed to angiotensin II (Ang II). Then, to confirm the ameliorative effects of σ1R stimulation in vivo, we administered SA4503 (1.0mg/kg) and the σ1R antagonist NE-100 (1.0mg/kg) orally to TAC mice for 4weeks (once daily).

RESULTS

σ1R stimulation with SA4503 significantly inhibited Ang II-induced cardiomyocyte hypertrophy. Ang II exposure for 72h impaired phenylephrine (PE)-induced Ca(2+) mobilization from the SR into both the cytosol and mitochondria. Treatment of cardiomyocytes with SA4503 largely restored PE-induced Ca(2+) mobilization into mitochondria. Exposure of cardiomyocytes to Ang II for 72h decreased basal ATP content and PE-induced ATP production concomitant with reduced mitochondrial size, while SA4503 treatment completely restored ATP production and mitochondrial size. Pretreatment with NE-100 or siRNA abolished these effects. Chronic SA4503 administration also significantly attenuated myocardial hypertrophy and restored ATP production in TAC mice. SA4503 administration also decreased hypertrophy-induced impairments in LV contractile function.

CONCLUSIONS

σ1R stimulation with the specific agonist SA4503 ameliorates cardiac hypertrophy and dysfunction by restoring both mitochondrial Ca(2+) mobilization and ATP production via σ1R stimulation.

GENERAL SIGNIFICANCE: Our observations suggest that σ1R stimulation represents a new therapeutic strategy to rescue the heart from hypertrophic dysfunction.