title: Disruption of CD38 gene enhances cardiac functions by elevating serum testosterone in the male null mice.
abstract: OBJECTIVE
  Gender-related phenotypes in the cardiovascular system have been observed in various genetically modified mice. Here, we report that cardiac functions are significantly improved only in male CD38-null mice and we explore the potential mechanisms of the sexual dimorphism mediated by CD38 deficiency.
  
  
  METHODS
  Cardiac functions of mice were measured by pressure-volume conductance catheter technique and echocardiography. Serum sex steroids were determined by radioimmunoassay. Relative mRNA levels of myocardial contractile-associated proteins in cardiomyocytes were analyzed by real-time PCR analysis. To clarify the effects of testosterone on the sexual dimorphism, flutamide, an androgen receptor antagonist, was subcutaneously infused into the male null mice for 6 weeks with an osmotic mini-pump.
  
  
  RESULTS
  The myocardial contractility, contraction and relaxation velocities were significantly enhanced only in male CD38-null mice, in which the levels of serum testosterone were markedly elevated. The elevated testosterone levels in the null mice were correlated to an obvious decrease in expression of androgen receptor and dramatic increases in expressions of major genes involved in myocardial contraction, including ryanodine receptor type 2 (RyR2), sarcoplasmic reticular Ca(2+) ATPase (SERCA2) and Na(+)/Ca(2+)-exchanger protein 1 (NCX1), and α myosin heavy chain (α-MHC). More importantly, all of the alternations that were observed in the male null mice were almost completely restored by flutamide administration.
  
  
  CONCLUSIONS
  Elevated serum level of testosterone in the male CD38(-/-) mice enhances cardiac functions through upregulation of major calcium regulatory proteins, which improve our understanding on sex disparities and molecular mechanisms in the incidence and manifestation of heart diseases.
authors.affiliation: Laboratory of Cardiovascular Disease, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Xiao
authors.forename: Lin
authors.initials: L
authors.lastname: Deng
authors.forename: Lun-Da
authors.initials: LD
authors.lastname: Gu
authors.forename: Zhi-Yun
authors.initials: ZY
authors.lastname: Guo
authors.forename: Zhi-Chao
authors.initials: ZC
authors.lastname: Zhou
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Xin
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics*; D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003285:Contractile Proteins / Q000235:genetics; D004452:Echocardiography; D005485:Flutamide / Q000494:pharmacology; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D012333:RNA, Messenger / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics; D013739:Testosterone / Q000097:blood*
chemical_list: D000726:Androgen Antagonists; D003285:Contractile Proteins; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013739:Testosterone; D005485:Flutamide; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium