Age-related changes in ischemic tolerance in male and female mouse hearts

Laura Willems, Amanda Zatta, Kirsten Holmgren, Kevin J. Ashton, John P. Headrick

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Abstract

Aging is associated with reduced tolerance to ischemic insult, and genesis of this intolerant phenotype is poorly understood. We characterized effects of aging and gender on cardiovascular function and cell damage during 20 min ischemia and 60 min reperfusion in isolated hearts from young adult (2-4 months), mature adult (8 months), middle-aged (12 months), aged (18 months), and senescent (24-28 months) C57/Bl6 mice. Aging substantially impaired recovery of ventricular contractility, with this change primarily evident within 12 months of age. In males ventricular developed pressure recovered to 72 ± 8 mmHg in young hearts vs. only 44 ± 7, 30 ± 3, 24 ± 5, and 27 ± 4 mmHg in mature, middle-aged, aged and senescent hearts, respectively. This pattern was largely due to worsened diastolic dysfunction. Coronary flow recovered to below pre-ischemic levels in all ages, correlating with contractile recovery. However, coronary dysfunction (impaired responses to 2-chloroadenosine and ADP) was unaltered by senescence. Lactate dehydrogenase (LDH) loss, a marker for oncosis, increased to middle-age (approximately twofold), then fell with further aging to a value no longer different from that in young adult hearts. Similar patterns of change were observed in female hearts, although LDH efflux was significantly lower in mature adult and middle-aged female vs. male hearts, with functional tolerance also tending to be greater at these ages (though not achieving significance). Overall, our data reveal age-related ischemic intolerance develops well before senescence, being primarily evident by "middle-age". Phenotypic changes appear selective for myocardial vs. vascular injury, and functional vs. oncotic injury. Similar changes occur in males and females, though there is evidence of a protected phenotype in mature to middle-aged female vs. male hearts.

Original languageEnglish
Pages (from-to)245-256
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume38
Issue number2
DOIs
Publication statusPublished - Feb 2005
Externally publishedYes

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L-Lactate Dehydrogenase
Young Adult
2-Chloroadenosine
Phenotype
Vascular System Injuries
Ventricular Pressure
Adenosine Diphosphate
Reperfusion
Ischemia
Wounds and Injuries

Cite this

Willems, Laura ; Zatta, Amanda ; Holmgren, Kirsten ; Ashton, Kevin J. ; Headrick, John P. / Age-related changes in ischemic tolerance in male and female mouse hearts. In: Journal of Molecular and Cellular Cardiology. 2005 ; Vol. 38, No. 2. pp. 245-256.
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Age-related changes in ischemic tolerance in male and female mouse hearts. / Willems, Laura; Zatta, Amanda; Holmgren, Kirsten; Ashton, Kevin J.; Headrick, John P.

In: Journal of Molecular and Cellular Cardiology, Vol. 38, No. 2, 02.2005, p. 245-256.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Age-related changes in ischemic tolerance in male and female mouse hearts

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AU - Zatta, Amanda

AU - Holmgren, Kirsten

AU - Ashton, Kevin J.

AU - Headrick, John P.

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N2 - Aging is associated with reduced tolerance to ischemic insult, and genesis of this intolerant phenotype is poorly understood. We characterized effects of aging and gender on cardiovascular function and cell damage during 20 min ischemia and 60 min reperfusion in isolated hearts from young adult (2-4 months), mature adult (8 months), middle-aged (12 months), aged (18 months), and senescent (24-28 months) C57/Bl6 mice. Aging substantially impaired recovery of ventricular contractility, with this change primarily evident within 12 months of age. In males ventricular developed pressure recovered to 72 ± 8 mmHg in young hearts vs. only 44 ± 7, 30 ± 3, 24 ± 5, and 27 ± 4 mmHg in mature, middle-aged, aged and senescent hearts, respectively. This pattern was largely due to worsened diastolic dysfunction. Coronary flow recovered to below pre-ischemic levels in all ages, correlating with contractile recovery. However, coronary dysfunction (impaired responses to 2-chloroadenosine and ADP) was unaltered by senescence. Lactate dehydrogenase (LDH) loss, a marker for oncosis, increased to middle-age (approximately twofold), then fell with further aging to a value no longer different from that in young adult hearts. Similar patterns of change were observed in female hearts, although LDH efflux was significantly lower in mature adult and middle-aged female vs. male hearts, with functional tolerance also tending to be greater at these ages (though not achieving significance). Overall, our data reveal age-related ischemic intolerance develops well before senescence, being primarily evident by "middle-age". Phenotypic changes appear selective for myocardial vs. vascular injury, and functional vs. oncotic injury. Similar changes occur in males and females, though there is evidence of a protected phenotype in mature to middle-aged female vs. male hearts.

AB - Aging is associated with reduced tolerance to ischemic insult, and genesis of this intolerant phenotype is poorly understood. We characterized effects of aging and gender on cardiovascular function and cell damage during 20 min ischemia and 60 min reperfusion in isolated hearts from young adult (2-4 months), mature adult (8 months), middle-aged (12 months), aged (18 months), and senescent (24-28 months) C57/Bl6 mice. Aging substantially impaired recovery of ventricular contractility, with this change primarily evident within 12 months of age. In males ventricular developed pressure recovered to 72 ± 8 mmHg in young hearts vs. only 44 ± 7, 30 ± 3, 24 ± 5, and 27 ± 4 mmHg in mature, middle-aged, aged and senescent hearts, respectively. This pattern was largely due to worsened diastolic dysfunction. Coronary flow recovered to below pre-ischemic levels in all ages, correlating with contractile recovery. However, coronary dysfunction (impaired responses to 2-chloroadenosine and ADP) was unaltered by senescence. Lactate dehydrogenase (LDH) loss, a marker for oncosis, increased to middle-age (approximately twofold), then fell with further aging to a value no longer different from that in young adult hearts. Similar patterns of change were observed in female hearts, although LDH efflux was significantly lower in mature adult and middle-aged female vs. male hearts, with functional tolerance also tending to be greater at these ages (though not achieving significance). Overall, our data reveal age-related ischemic intolerance develops well before senescence, being primarily evident by "middle-age". Phenotypic changes appear selective for myocardial vs. vascular injury, and functional vs. oncotic injury. Similar changes occur in males and females, though there is evidence of a protected phenotype in mature to middle-aged female vs. male hearts.

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