title: Pharmacological options to protect the aged heart from ischemia and reperfusion injury by targeting the PKA-BK(Ca) signaling pathway.
abstract: The beneficial effects of many cardioprotective strategies including ischemic or pharmacological conditioning are reduced in the aged heart. The underlying reason(s) for the age-dependent loss of cardioprotection is unclear. Recently, we demonstrated that protein kinase A (PKA) dependent cardioprotection is lost in the aged heart. However, activation of large-conductance Ca(2+)-sensitive K(+) (BK(Ca)) channels, a putative PKA downstream target, initiated cardioprotection also in the aged heart. Therefore, we aimed to investigate whether 1) BK(Ca) channels are critically involved in PKA activation induced cardioprotection and 2) the age-dependent loss of cardioprotection is caused by differences in PKA regulation. Using an in vivo rat model with regional myocardial ischemia, we treated young (2-4 months) and aged (22-24 months) Wistar rats with PKA activator forskolin, BK(Ca) channel activator NS1619 and/or BK(Ca) channel blocker iberiotoxin. Forskolin induced infarct size reduction was 1) age-dependent and 2) prevented by iberiotoxin. The effect of forskolin on myocardial PKA activity was comparable in young and aged animals. In addition, NS1619 initiated cardioprotection also in the aged heart both when administered before ischemia and during early reperfusion phase. Activation of BK(Ca) channels is critically involved in forskolin induced cardioprotection. The age-dependency of forskolin induced cardioprotection is not caused by age-dependent differences in PKA activation. Pharmacological targeting of BK(Ca) channels before or after myocardial ischemia is a promising therapeutic strategy to protect the aged heart from ischemia and reperfusion injury.
authors.affiliation: Department of Cardiovascular Physiology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany; Department of Anesthesiology, University Hospital Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Electronic address: andre.heinen@uni-duesseldorf.de.
authors.forename: Andre
authors.initials: A
authors.lastname: Heinen
authors.affiliation: Department of Anesthesiology, University Hospital Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Electronic address: martin.stroethoff@uni-duesseldorf.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Ströthoff
authors.affiliation: Department of Anesthesiology, University Hospital Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Electronic address: anika.schmidt@uni-duesseldorf.de.
authors.forename: Anika
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Department of Anesthesiology, University Hospital Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Electronic address: nadine.stracke@med.uni-duesseldorf.de.
authors.forename: Nadine
authors.initials: N
authors.lastname: Stracke
authors.affiliation: Department of Anesthesiology, University Hospital Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Electronic address: friederike.behmenburg@med.uni-duesseldorf.de.
authors.forename: Friederike
authors.initials: F
authors.lastname: Behmenburg
authors.affiliation: Department of Anesthesiology, University Hospital Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Electronic address: inge.bauer@med.uni-duesseldorf.de.
authors.forename: Inge
authors.initials: I
authors.lastname: Bauer
authors.affiliation: Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 9, 1100 DD Amsterdam, The Netherlands. Electronic address: m.w.hollmann@amc.uva.nl.
authors.forename: Markus W
authors.initials: MW
authors.lastname: Hollmann
authors.affiliation: Department of Anesthesiology, University Hospital Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Electronic address: ragnar.huhn@med.uni-duesseldorf.de.
authors.forename: Ragnar
authors.initials: R
authors.lastname: Huhn
mesh_terms: D000367:Age Factors; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000378:metabolism; D008297:Male; D058990:Molecular Targeted Therapy; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001562:Benzimidazoles; D020536:Enzyme Activators; D051036:Large-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; C086491:NS 1619; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Aging; Cardioprotection; Large-conductance Ca(2+) sensitive K(+) channel; Myocardial infarction; Protein kinase A