title: Stimulation of σ1-receptor restores abnormal mitochondrial Ca²⁺ mobilization and ATP production following cardiac hypertrophy.
abstract: 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.
  
  
  CONCLUSIONS
  Our observations suggest that σ1R stimulation represents a new therapeutic strategy to rescue the heart from hypertrophic dysfunction.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tagashira
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.forename: Ying-Mei
authors.initials: YM
authors.lastname: Lu
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kanai
authors.forename: Feng
authors.initials: F
authors.lastname: Han
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006332:Cardiomegaly / Q000188:drug therapy* / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000032:analysis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D017480:Receptors, sigma / Q000819:agonists / Q000032:analysis / Q000502:physiology*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; C580990:Ip3r2 protein, mouse; D010879:Piperazines; D017480:Receptors, sigma; D000255:Adenosine Triphosphate; C101789:SA 4503; D002118:Calcium