Beta-Adrenoceptor Stimulation Reveals Ca2+ Waves and Sarcoplasmic Reticulum Ca2+ Depletion in Left Ventricular Cardiomyocytes from Post-Infarction Rats with and without Heart Failure.
Abnormal cellular Ca2+ handling contributes to both contractile dysfunction and arrhythmias in heart failure. Reduced Ca2+ transient amplitude due to decreased sarcoplasmic reticulum Ca2+ content is a common finding in heart failure models. However, heart failure models also show increased propensity for diastolic Ca2+ release events which occur when sarcoplasmic reticulum Ca2+ content exceeds a certain threshold level. Such Ca2+ release events can initiate arrhythmias. In this study we aimed to investigate if both of these aspects of altered Ca2+ homeostasis could be found in left ventricular cardiomyocytes from rats with different states of cardiac function six weeks after myocardial infarction when compared to sham-operated controls. Video edge-detection, whole-cell Ca2+ imaging and confocal line-scan imaging were used to investigate cardiomyocyte contractile properties, Ca2+ transients and Ca2+ waves. In baseline conditions, i.e. without beta-adrenoceptor stimulation, cardiomyocytes from rats with large myocardial infarction, but without heart failure, did not differ from sham-operated animals in any of these aspects of cellular function. However, when exposed to beta-adrenoceptor stimulation, cardiomyocytes from both non-failing and failing rat hearts showed decreased sarcoplasmic reticulum Ca2+ content, decreased Ca2+ transient amplitude, and increased frequency of Ca2+ waves. These results are in line with a decreased threshold for diastolic Ca2+ release established by other studies. In the present study, factors that might contribute to a lower threshold for diastolic Ca2+ release were increased THR286 phosphorylation of Ca2+/calmodulin-dependent protein kinase II and increased protein phosphatase 1 abundance. In conclusion, this study demonstrates both decreased sarcoplasmic reticulum Ca2+ content and increased propensity for diastolic Ca2+ release events in ventricular cardiomyocytes from rats with heart failure after myocardial infarction, and that these phenomena are also found in rats with large myocardial infarctions without heart failure development. Importantly, beta-adrenoceptor stimulation is necessary to reveal these perturbations in Ca2+ handling after a myocardial infarction.
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
Mani
http://orcid.org/0000-0001-6015-7411
M
Sadredini
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
Tore Kristian
TK
Danielsen
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|Bjørknes College, Oslo, Norway.
Jan Magnus
JM
Aronsen
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
Ravinea
R
Manotheepan
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
Karina
K
Hougen
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
Ivar
I
Sjaastad
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.|KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.|Clinic for Internal Medicine, Lovisenberg Diakonale Hospital, Oslo, Norway.
Mathis Korseberg
MK
Stokke
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D006333:Heart Failure / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000473:pathology*
D011943:Receptors, Adrenergic, beta; D002118:Calcium