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This Article Full Text Full Text (PDF) All Versions of this Article: 289/1/H160    most recent 00895.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Dworschak, M. Articles by Hannon, J. D. Search for Related Content PubMed PubMed Citation Articles by Dworschak, M. Articles by Hannon, J. D.

Increased tolerance to hypoxic metabolic inhibition and reoxygenation of cardiomyocytes from apolipoprotein E-deficient mice

¹Department of Anesthesia Research, Mayo Foundation, Rochester, Minnesota; ²Division of Cardiothoracic and Vascular Anesthesia and Intensive Care, University Hospital Vienna, Vienna, Austria; and ³Department of Anaesthesiology and Intensive Care, University of Münster, Münster, Germany

Submitted 25 August 2004 ; accepted in final form 23 February 2005

Although hypercholesterolemia is a strong risk factor for cardiovascular disease, it has in some instances paradoxically been associated with reduced infarct size and preserved contractile function in isolated hearts after ischemia and reperfusion. To elucidate potential cellular protective mechanisms, myocytes of hypercholesterolemic apolipoprotein E-deficient (ApoE^–/–) and wild-type mice were subjected to hypoxic metabolic inhibition (I) with subsequent reoxygenation (R). Intracellular Ca²⁺ concentration ([Ca²⁺]_i) and pH (pH_i) were monitored as well as cell length and arrhythmic events. Force measurements in papillary muscles were also recorded, and myocardial expression of Na⁺/H⁺ exchanger 1 (NHE1) and three Ca²⁺ handling proteins [sarco(endo)plasmic reticulum Ca²⁺-ATPase, Na⁺/Ca²⁺ exchanger, and plasma membrane Ca²⁺-ATPase] was quantified. After 30 min of I and 35 min of R, Ca²⁺ overload was more pronounced in wild-type cells (P < 0.05). In these myocytes, pH_i also dropped faster and remained below those values determined in ApoE^–/– cells (P < 0.05). Furthermore, more wild-type myocytes remained in a contracted state (P < 0.05). This group also showed a higher incidence of arrhythmic events during R (P < 0.05). No group difference was found in the expression of the Ca²⁺ handling proteins. However, NHE1 protein was downregulated in hearts of ApoE^–/– mice (P < 0.05). Histological results depict hyperplasia in ApoE^–/– hearts without atherosclerosis of the coronaries. Contractile dysfunction was not observed in papillary muscles from ApoE^–/– hearts. Our results suggest that downregulated myocardial NHE1 expression in hypercholesterolemic ApoE^–/– mice could have contributed to increased tolerance to I/R. It remains to be elucidated whether NHE1 downregulation is a unique feature of these genetically altered animals.

hypoxic metabolic inhibition and reoxygenation; intracellular Ca²⁺ and pH handling; Na⁺/H⁺ exchanger; ventricular myocytes