title: Myocardial and cardiomyocyte stress resilience is enhanced in aromatase-deficient female mouse hearts through CaMKIIδ activation.
abstract: The role of sex steroids in cardioprotection is contentious, with large clinical trials investigating hormone supplementation failing to deliver outcomes expected from observational studies. Mechanistic understanding of androgen/estrogen myocardial actions is lacking. Using a genetic model of aromatase tissue deficiency (ArKO) in female mice, the goal of this investigation was to evaluate the capacity of a shift in cardiac endogenous steroid conversion to influence ischemia-reperfusion resilience by optimizing cardiomyocyte Ca2+ handling responses. In isolated normoxic cardiomyocytes, basal Ca2+ transient amplitude and extent of shortening were greater in ArKO myocytes, with preservation of diastolic Ca2+ levels. Isolated ArKO cardiomyocytes exposed to a high Ca2+ load exhibited greater Ca2+ transient and contractile amplitudes, associated with a greater postrest spontaneous sarcoplasmic reticulum Ca2+ load-release. Microarray differential gene expression analysis of normoxic ventricular tissues from ArKO vs wild-type identified a significant influence of aromatase on genes involved in cardiac Ca2+ handling and signaling [including calmodulin dependent kinase II (CaMKII)-δ], myofilament structure and function, glucose uptake and signaling, and enzymes controlling phosphorylation-specific posttranslational modification status. CaMKII expression was not changed in ventricular tissues, although CaMKIIδ activation and phosphorylation of downstream targets was enhanced in ArKO hearts subjected to ischemia-reperfusion. Overall, this investigation shows that relative withdrawal of estrogen in favor of testosterone through genetically induced tissue aromatase deficiency in females modifies the gene expression profile to effect inotropic support via optimized Ca2+ handling in response to stress, with a modest impact on basal function. Consideration of aromatase inhibition, acutely or chronically, may have a role in cardioprotection, of particular relevance to women.
authors.affiliation: Cardiac Phenomics Laboratory (J.R.B., G.B.B., A.C.W., A.J.A.R., C.L.C., K.M.M., L.M.D.D.), Department of Physiology, and The Florey Institute of Neuroscience and Mental Health (W.C.B.), University of Melbourne, Victoria 3010, Australia; Monash Institute of Medical Research-Prince Henry's Institute of Medical Research (E.R.S.), Clayton 3168, Victoria, Australia; and Department of Physiology (K.M.M.), University of Auckland, 1142 Auckland, New Zealand.
authors.forename: James R
authors.initials: JR
authors.lastname: Bell
authors.forename: Gabriel B
authors.initials: GB
authors.lastname: Bernasochi
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Wollermann
authors.forename: Antonia J A
authors.initials: AJ
authors.lastname: Raaijmakers
authors.forename: Wah Chin
authors.initials: WC
authors.lastname: Boon
authors.forename: Evan R
authors.initials: ER
authors.lastname: Simpson
authors.forename: Claire L
authors.initials: CL
authors.lastname: Curl
authors.forename: Kimberley M
authors.initials: KM
authors.lastname: Mellor
authors.forename: Lea M D
authors.initials: LM
authors.lastname: Delbridge
mesh_terms: D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D001835:Body Weight / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010766:Phosphorylation; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D001141:Aromatase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium