title: Ageing-related cardiomyocyte functional decline is sex and angiotensin II dependent.
abstract: Clinically, heart failure is an age-dependent pathological phenomenon and displays sex-specific characteristics. The renin-angiotensin system mediates cardiac pathology in heart failure. This study investigated the sexually dimorphic functional effects of ageing combined with angiotensin II (AngII) on cardiac muscle cell function, twitch and Ca(2+)-handling characteristics of isolated cardiomyocytes from young (~13 weeks) and aged (~87 weeks) adult wild type (WT) and AngII-transgenic (TG) mice. We hypothesised that AngII-induced contractile impairment would be exacerbated in aged female cardiomyocytes and linked to Ca(2+)-handling disturbances. AngII-induced cardiomyocyte hypertrophy was evident in young adult mice of both sexes and accentuated by age (aged adult ~21-23 % increases in cell length relative to WT). In female AngII-TG mice, ageing was associated with suppressed cardiomyocyte contractility (% shortening, maximum rate of shortening, maximum rate of relaxation). This was associated with delayed cytosolic Ca(2+) removal during twitch relaxation (Tau ~20 % increase relative to young adult female WT), and myofilament responsiveness to Ca(2+) was maintained. In contrast, aged AngII-TG male cardiomyocytes exhibited peak shortening equivalent to young TG; yet, myofilament Ca(2+) responsiveness was profoundly reduced with ageing. Increased pro-arrhythmogenic spontaneous activity was evident with age and cardiac AngII overexpression in male mice (42-55 % of myocytes) but relatively suppressed in female aged transgenic mice. Female myocytes with elevated AngII appear more susceptible to an age-related contractile deficit, whereas male AngII-TG myocytes preserve contractile function with age but exhibit desensitisation of myofilaments to Ca(2+) and a heightened vulnerability to arrhythmic activity. These findings support the contention that sex-specific therapies are required for the treatment of age-progressive heart failure.
authors.affiliation: Department of Physiology, University of Melbourne, Melbourne, VIC, Australia, k.mellor@auckland.ac.nz.
authors.forename: Kimberley M
authors.initials: KM
authors.lastname: Mellor
authors.forename: Claire L
authors.initials: CL
authors.lastname: Curl
authors.forename: Chanchal
authors.initials: C
authors.lastname: Chandramouli
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedrazzini
authors.forename: Igor R
authors.initials: IR
authors.lastname: Wendt
authors.forename: Lea M D
authors.initials: LM
authors.lastname: Delbridge
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000804:Angiotensin II / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D012313:RNA / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000804:Angiotensin II; D012313:RNA