Hypertensive hypertrophied myocardium is vulnerable to infarction and refractory to erythropoietin-induced protection.
The objective of this study was to examine the hypothesis that hypertensive hypertrophy is vulnerable to infarction and defective in cytoprotective mechanisms by modification of intracellular signaling and mitochondrial proteins. Myocardial infarction was induced by 20-minute coronary occlusion/reperfusion in spontaneously hypertensive stroke-prone rats (SHR-SPs) and their controls (Wistar-Kyoto rats [WKYs]). Infarct size expressed as a percentage of area-at-risk was larger by 29% in SHR-SPs than in WKYs. Pretreatment with erythropoietin (EPO) significantly limited infarct size in WKYs but not in SHR-SPs. Ca(2+) retention capacity of mitochondria, an index of the threshold for opening of the mitochondrial permeability transition pore, on reperfusion was reduced in SHR-SPs compared with that in WKYs. Suppression of reactive oxygen species by N-(2-mercaptopropionyl)-glycine increased Ca(2+) retention capacity after reperfusion and limited infarct size in SHR-SPs to levels in WKYs. EPO induced phosphorylation of Akt, extracellular signal-related kinase, and glycogen synthase kinase-3β in the myocardium in both WKYs and SHR-SPs. EPO enhanced interaction of phospho-glycogen synthase kinase-3β and adenine nucleotide translocase on reperfusion in WKYs, although such an effect of EPO was not detected in SHR-SPs. The results suggest that enhanced opening of mitochondrial permeability transition pores by reactive oxygen species and modification of the signal downstream of phospho-glycogen synthase kinase-3β in the mitochondria underlie the increased vulnerability to infarction and the lack of anti-infarct tolerance by EPO, respectively, in hypertensive hypertrophied hearts.
Second Department of Internal Medicine, Sapporo Medical University, School of Medicine, Sapporo, Japan.
Toshiyuki
T
Yano
Takayuki
T
Miki
Masaya
M
Tanno
Atsushi
A
Kuno
Takahito
T
Itoh
Akifumi
A
Takada
Tatsuya
T
Sato
Hidemichi
H
Kouzu
Kazuaki
K
Shimamoto
Tetsuji
T
Miura
D000818:Animals; D002118:Calcium / Q000032:analysis; D006332:Cardiomegaly / Q000209:etiology*; D004921:Erythropoietin / Q000627:therapeutic use*; D006973:Hypertension / Q000150:complications*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000032:analysis; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000209:etiology* / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D012307:Risk Factors; D008625:Tiopronin / Q000494:pharmacology
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D004921:Erythropoietin; D000226:Mitochondrial ADP, ATP Translocases; D008625:Tiopronin; D017346:Protein Serine-Threonine Kinases; D002118:Calcium