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Ageing-related cardiomyocyte functional decline is sex and angiotensin II dependent

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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 Ca2+-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 Ca2+-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 Ca2+ removal during twitch relaxation (Tau ~20 % increase relative to young adult female WT), and myofilament responsiveness to Ca2+ was maintained. In contrast, aged AngII-TG male cardiomyocytes exhibited peak shortening equivalent to young TG; yet, myofilament Ca2+ 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 Ca2+ 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.

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References

  • Ahmed A (2003) American College of Cardiology/American Heart Association Chronic Heart Failure Evaluation and Management guidelines: relevance to the geriatric practice. J Am Geriatr Soc 51:123–126

    Article  PubMed  Google Scholar 

  • Asp ML, Martindale JJ, Heinis FI, Wang W, Metzger JM (2012) Calcium mishandling in diastolic dysfunction: mechanisms and potential therapies. Biochim Biophys Acta

  • Baker KM, Chernin MI, Schreiber T, Sanghi S, Haiderzaidi S, Booz GW, Dostal DE, Kumar R (2004) Evidence of a novel intracrine mechanism in angiotensin II-induced cardiac hypertrophy. Regul Pept 120:5–13

    Article  CAS  PubMed  Google Scholar 

  • Barsheshet A, Brenyo A, Goldenberg I, Moss AJ (2012) Sex-related differences in patients' responses to heart failure therapy. Nat Rev Cardiol 9:234–242

    Article  CAS  PubMed  Google Scholar 

  • Bell JR, Bernasochi GB, Varma U, Raaijmakers AJ, Delbridge LM (2013) Sex and sex hormones in cardiac stress-mechanistic insights. J Steroid Biochem Mol Biol

  • Bers DM (2001) Excitation-contraction coupling and cardiac contractile force, 2nd edn. Kluwer Academic, Dordrecht

  • Bhatnagar GM, Walford GD, Beard ES, Humphreys S, Lakatta EG (1984) ATPase activity and force production in myofibrils and twitch characteristics in intact muscle from neonatal, adult, and senescent rat myocardium. J Mol Cell Cardiol 16:203–218

    Article  CAS  PubMed  Google Scholar 

  • Brown RD, Hilliard LM, Head GA, Jones ES, Widdop RE, Denton KM (2012) Sex differences in the pressor and tubuloglomerular feedback response to angiotensin II. Hypertension 59:129–135

    Article  CAS  PubMed  Google Scholar 

  • Bupha-Intr T, Laosiripisan J, Wattanapermpool J (2009) Moderate intensity of regular exercise improves cardiac SR Ca2+ uptake activity in ovariectomized rats. J Appl Physiol 107:1105–1112

    Article  CAS  PubMed  Google Scholar 

  • Bupha-Intr T, Wattanapermpool J (2006) Regulatory role of ovarian sex hormones in calcium uptake activity of cardiac sarcoplasmic reticulum. Am J Physiol Heart Circ Physiol 291:H1101–H1108

    Article  CAS  PubMed  Google Scholar 

  • Ceylan-Isik AF, Li Q, Ren J (2011) Insulin-like growth factor I (IGF-1) deficiency ameliorates sex difference in cardiac contractile function and intracellular Ca(2+) homeostasis. Toxicol Lett 206:130–138

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • de Giuli F, Khaw KT, Cowie MR, Sutton GC, Ferrari R, Poole-Wilson PA (2005) Incidence and outcome of persons with a clinical diagnosis of heart failure in a general practice population of 696,884 in the United Kingdom. Eur J Heart Fail 7:295–302

    Article  PubMed  Google Scholar 

  • Domenighetti AA, Boixel C, Cefai D, Abriel H, Pedrazzini T (2007) Chronic angiotensin II stimulation in the heart produces an acquired long QT syndrome associated with IK1 potassium current downregulation. J Mol Cell Cardiol 42:63–70

    Article  CAS  PubMed  Google Scholar 

  • Domenighetti AA, Pedrazzini T, Delbridge LMD (2001) Abnormal contractile function in cardiomyocytes from transgenic mice overexpressing AngII in the heart. Proc. Renin Angiotensin-Aldosterone System Satellite of the XXXIV. Congress of the International Union of Physiological Science, Melbourne

    Google Scholar 

  • Domenighetti AA, Wang Q, Egger M, Richards SM, Pedrazzini T, Delbridge LM (2005) Angiotensin II-mediated phenotypic cardiomyocyte remodeling leads to age-dependent cardiac dysfunction and failure. Hypertension 46:426–432

    Article  CAS  PubMed  Google Scholar 

  • Dostal DE, Baker KM (1993) Evidence for a role of an intracardiac renin-angiotensin system in normal and failing hearts. Trends Cardiovasc Med 3:67–74

    Article  CAS  PubMed  Google Scholar 

  • Durand JB (2002) Current guidelines in heart failure management. Ethn Dis 12:S1-3-11

    Google Scholar 

  • Feldmer M, Kaling M, Takahashi S, Mullins JJ, Ganten D (1991) Glucocorticoid- and estrogen-responsive elements in the 5'-flanking region of the rat angiotensinogen gene. J Hypertens 9:1005–1012

    Article  CAS  PubMed  Google Scholar 

  • Gomez AM, Richard S (2004) Mutant cardiac ryanodine receptors and ventricular arrhythmias: is 'gain-of-function' obligatory? Cardiovasc Res 64:3–5

    Article  CAS  PubMed  Google Scholar 

  • Gusev K, Domenighetti AA, Delbridge LM, Pedrazzini T, Niggli E, Egger M (2009) Angiotensin II-mediated adaptive and maladaptive remodeling of cardiomyocyte excitation-contraction coupling. Circ Res 105:42–50

    Article  CAS  PubMed  Google Scholar 

  • Heymes C, Silvestre JS, Llorens-Cortes C, Chevalier B, Marotte F, Levy BI, Swynghedauw B, Samuel JL (1998) Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes. Endocrinology 139:2579–2587

    CAS  PubMed  Google Scholar 

  • Heymes C, Swynghedauw B, Chevalier B (1994) Activation of angiotensinogen and angiotensin-converting enzyme gene expression in the left ventricle of senescent rats. Circulation 90:1328–1333

    Article  CAS  PubMed  Google Scholar 

  • Howlett SE (2010) Age-associated changes in excitation-contraction coupling are more prominent in ventricular myocytes from male rats than in myocytes from female rats. Am J Physiol Heart Circ Physiol 298:H659–H670

    Article  CAS  PubMed  Google Scholar 

  • Huggins CE, Curl CL, Patel R, McLennan PL, Theiss ML, Pedrazzini T, Pepe S, Delbridge LM (2009) Dietary fish oil is antihypertrophic but does not enhance postischemic myocardial function in female mice. Am J Physiol Heart Circ Physiol 296:H957–H966

    Article  CAS  PubMed  Google Scholar 

  • Huggins CE, Domenighetti AA, Pedrazzini T, Pepe S, Delbridge LM (2003) Elevated intracardiac angiotensin II leads to cardiac hypertrophy and mechanical dysfunction in normotensive mice. J Renin Angiotensin Aldosterone Syst 4:186–190

    Article  CAS  PubMed  Google Scholar 

  • Ikenouchi H, Barry WH, Bridge JH, Weinberg EO, Apstein CS, Lorell BH (1994) Effects of angiotensin II on intracellular Ca2+ and pH in isolated beating rabbit hearts and myocytes loaded with the indicator indo-1. J Physiol 480(Pt 2):203–215

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kannel WB, Wilson PW, D'Agostino RB, Cobb J (1998) Sudden coronary death in women. Am Heart J 136:205–212

    Article  CAS  PubMed  Google Scholar 

  • Kockskamper J, Zima AV, Blatter LA (2005) Modulation of sarcoplasmic reticulum Ca2+ release by glycolysis in cat atrial myocytes. J Physiol 564:697–714

    Article  PubMed Central  PubMed  Google Scholar 

  • Kunstyr I, Leuenberger HG (1975) Gerontological data of C57BL/6 J mice. I. Sex differences in survival curves. J Gerontol 30:157–162

    Article  CAS  PubMed  Google Scholar 

  • Larson MG (1995) Assessment of cardiovascular risk factors in the elderly: the Framingham Heart Study. Stat Med 14:1745–1756

    Article  CAS  PubMed  Google Scholar 

  • Lindpaintner K, Ganten D (1991) The cardiac renin-angiotensin system. An appraisal of present experimental and clinical evidence. Circ Res 68:905–921

    Article  CAS  PubMed  Google Scholar 

  • Liu CG, Xu KQ, Xu X, Huang JJ, Xiao JC, Zhang JP, Song HP (2007) 17Beta-oestradiol regulates the expression of Na+/K + -ATPase beta1-subunit, sarcoplasmic reticulum Ca2 + -ATPase and carbonic anhydrase iv in H9C2 cells. Clin Exp Pharmacol Physiol 34:998–1004

    Article  CAS  PubMed  Google Scholar 

  • Malhotra A, Kang BP, Cheung S, Opawumi D, Meggs LG (2001) Angiotensin II promotes glucose-induced activation of cardiac protein kinase C isozymes and phosphorylation of troponin I. Diabetes 50:1918–1926

    Article  CAS  PubMed  Google Scholar 

  • Maric C (2005) Sex differences in cardiovascular disease and hypertension: involvement of the renin-angiotensin system. Hypertension 46:475–476

    Article  CAS  PubMed  Google Scholar 

  • Mattiazzi A (1997) Positive inotropic effect of angiotensin II. Increases in intracellular Ca2+ or changes in myofilament Ca2+ responsiveness? J Pharmacol Toxicol Methods 37:205–214

    Article  CAS  PubMed  Google Scholar 

  • Mazzolai L, Nussberger J, Aubert JF, Brunner DB, Gabbiani G, Brunner HR, Pedrazzini T (1998) Blood pressure-independent cardiac hypertrophy induced by locally activated renin-angiotensin system. Hypertension 31:1324–1330

    Article  CAS  PubMed  Google Scholar 

  • Mazzolai L, Pedrazzini T, Nicoud F, Gabbiani G, Brunner HR, Nussberger J (2000) Increased cardiac angiotensin II levels induce right and left ventricular hypertrophy in normotensive mice. Hypertension 35:985–991

    Article  CAS  PubMed  Google Scholar 

  • Mellor KM, Wendt IR, Ritchie RH, Delbridge LM (2012) Fructose diet treatment in mice induces fundamental disturbance of cardiomyocyte Ca2+ handling and myofilament responsiveness. Am J Physiol Heart Circ Physiol 302:H964–H972

    Article  CAS  PubMed  Google Scholar 

  • Parks RJ, Howlett SE (2013) Sex differences in mechanisms of cardiac excitation-contraction coupling. Pflugers Arch 465:747–763

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pellieux C, Aasum E, Larsen TS, Montessuit C, Papageorgiou I, Pedrazzini T, Lerch R (2006) Overexpression of angiotensinogen in the myocardium induces downregulation of the fatty acid oxidation pathway. J Mol Cell Cardiol 41:459–466

    Article  CAS  PubMed  Google Scholar 

  • Pellieux C, Sauthier T, Aubert JF, Brunner HR, Pedrazzini T (2000) Angiotensin II-induced cardiac hypertrophy is associated with different mitogen-activated protein kinase activation in normotensive and hypertensive mice. J Hypertens 18:1307–1317

    Article  CAS  PubMed  Google Scholar 

  • Rabi DM, Khan N, Vallee M, Hladunewich MA, Tobe SW, Pilote L (2008) Reporting on sex-based analysis in clinical trials of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker efficacy. Can J Cardiol 24:491–496

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Regitz-Zagrosek V, Lehmkuhl E (2005) Heart failure and its treatment in women. Role of hypertension, diabetes, and estrogen. Herz 30:356–367

    Article  PubMed  Google Scholar 

  • Rivard K, Grandy SA, Douillette A, Paradis P, Nemer M, Allen BG, Fiset C (2011) Overexpression of type 1 angiotensin II receptors impairs excitation-contraction coupling in the mouse heart. Am J Physiol Heart Circ Physiol 301:H2018–H2027

    Article  CAS  PubMed  Google Scholar 

  • Roger VL, Weston SA, Redfield MM, Hellermann-Homan JP, Killian J, Yawn BP, Jacobsen SJ (2004) Trends in heart failure incidence and survival in a community-based population. Jama 292:344–350

    Article  CAS  PubMed  Google Scholar 

  • Seeland U and Regitz-Zagrosek V (2012) Sex and gender differences in cardiovascular drug therapy. Handb Exp Pharmacol 211–236

  • Shekelle PG, Rich MW, Morton SC, Atkinson CS, Tu W, Maglione M, Rhodes S, Barrett M, Fonarow GC, Greenberg B, Heidenreich PA, Knabel T, Konstam MA, Steimle A, Warner Stevenson L (2003) Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials. J Am Coll Cardiol 41:1529–1538

    Article  CAS  PubMed  Google Scholar 

  • Spurgeon HA, duBell WH, Stern MD, Sollott SJ, Ziman BD, Silverman HS, Capogrossi MC, Talo A, Lakatta EG (1992) Cytosolic calcium and myofilaments in single rat cardiac myocytes achieve a dynamic equilibrium during twitch relaxation. J Physiol 447:83–102

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sullivan JC (2008) Sex and the renin-angiotensin system: inequality between the sexes in response to RAS stimulation and inhibition. Am J Physiol Regul Integr Comp Physiol 294:R1220–R1226

    Article  CAS  PubMed  Google Scholar 

  • Unger T, Li J (2004) The role of the renin-angiotensin-aldosterone system in heart failure. J Renin Angiotensin Aldosterone Syst 5(Suppl 1):S7–S10

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Physiology, University of Melbourne, Melbourne, VIC, Australia

    Kimberley M. Mellor, Claire L. Curl, Chanchal Chandramouli & Lea M. D. Delbridge

  2. Department of Medicine, University of Lausanne, Lausanne, Switzerland

    Thierry Pedrazzini

  3. Department of Physiology, Monash University, Melbourne, VIC, Australia

    Igor R. Wendt

  4. Department of Physiology, University of Auckland, Auckland, New Zealand

    Kimberley M. Mellor

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  1. Kimberley M. Mellor
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  2. Claire L. Curl
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  3. Chanchal Chandramouli
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  4. Thierry Pedrazzini
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  5. Igor R. Wendt
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  6. Lea M. D. Delbridge
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Correspondence to Lea M. D. Delbridge.

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Mellor, K.M., Curl, C.L., Chandramouli, C. et al. Ageing-related cardiomyocyte functional decline is sex and angiotensin II dependent. AGE 36, 9630 (2014). https://doi.org/10.1007/s11357-014-9630-7

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