Opposing effects of age and calorie restriction on molecular determinants of myocardial ischemic tolerance

Peart, Jason N., See Hoe, Louise, Pepe, Salvatore, Johnson, Peter V., and Headrick, John P. (2012) Opposing effects of age and calorie restriction on molecular determinants of myocardial ischemic tolerance. Rejuvenation Research, 15 (1). pp. 59-70.

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We test the hypothesis that moderate calorie restriction (CR) reverses negative influences of age on molecular determinants of myocardial stress resistance. Postischemic contractile dysfunction, cellular damage, and expression of regulators of autophagy/apoptosis and of prosurvival and prodeath kinases were assessed in myocardium from young adult (YA; 2- to 4-month-old) and middle-aged (MA; 12-month-old) mice, and MA mice subjected to 14 weeks of 40% CR (MA-CR). Ventricular dysfunction after 25%±2%), as was cell death indicated by troponin I (TnI) efflux (1,701±214 ng vs. 785±102 ng in YA). MA hearts exhibited 30% and 65% reductions in postischemic Beclin1 and Parkin, respectively, yet 50% lower proapoptotic Bax and 85% higher antiapoptotic Bcl2, increasing the Bcl2/Bax ratio. Age did not influence Akt or p38-mitogen-activated protein kinase (MAPK) expression; reduced expression of increasingly phosphorylated ribosomal protein S6 kinase (p70S6K), increased expression of dephosphorylated glycogen synthase kinase 3β (GSK3β) and enhanced postischemic p38-MAPK phosphorylation. CR countered the age-related decline in ischemic tolerance, improving contractile recovery (60%±4%) and reducing cell death (123±22 ng of TnI). Protection was not associated with changes in Parkin or Bax, whereas CR partially limited the age-related decline in Beclin1 and further increased Bcl2. CR counteracted age-related changes in p70S6K, increased Akt levels, and reduced p38-MAPK (albeit increasing preischemic phosphorylation), and paradoxically reduced postischemic GSK3β phosphorylation. In summary, moderate age worsens cardiac ischemic tolerance; this is associated with reduced expression of autophagy regulators, dysregulation of p70S6K and GSK3β, and postischemic p38-MAPK activation. CR counters age effects on postischemic dysfunction/cell death; this is associated with reversal of age effects on p70S6K, augmentation of Akt and Bcl2 levels, and preischemic p38-MAPK activation. Age and CR thus impact on distinct determinants of ischemic tolerance, although p70S6K signaling presents a point of convergence.

Item ID: 38920
Item Type: Article (Research - C1)
ISSN: 1557-8577
Funders: National Heart Foundation of Australia (NHF), National Health and Medical Research Council of Australia (NHMRC)
Projects and Grants: NHF G08B3971, NHF G05B2029
Date Deposited: 23 Jun 2015 03:23
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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