Cardiomyocyte Mineralocorticoid Receptor Activation Impairs Acute Cardiac Functional Recovery After Ischemic Insult.
Loss of mineralocorticoid receptor signaling selectively in cardiomyocytes can ameliorate cardiac fibrotic and inflammatory responses caused by excess mineralocorticoids. The aim of this study was to characterize the role of cardiomyocyte mineralocorticoid receptor signaling in ischemia-reperfusion injury and recovery and to identify a role of mineralocorticoid receptor modulation of cardiac function. Wild-type and cardiomyocyte mineralocorticoid receptor knockout mice (8 weeks) were uninephrectomized and maintained on (1) high salt (0.9% NaCl, 0.4% KCl) or (2) high salt plus deoxycorticosterone pellet (0.3 mg/d, 0.9% NaCl, 0.4% KCl). After 8 weeks of treatment, hearts were isolated and subjected to 20 minutes of global ischemia plus 45 minutes of reperfusion. Mineralocorticoid excess increased peak contracture during ischemia regardless of genotype. Recovery of left ventricular developed pressure and rates of contraction and relaxation post ischemia-reperfusion were greater in knockout versus wild-type hearts. The incidence of arrhythmic activity during early reperfusion was significantly higher in wild-type than in knockout hearts. Levels of autophosphorylated Ca(2+)/calmodulin protein kinase II (Thr287) were elevated in hearts from wild-type versus knockout mice and associated with increased sodium hydrogen exchanger-1 expression. These findings demonstrate that cardiomyocyte-specific mineralocorticoid receptor-dependent signaling contributes to electromechanical vulnerability in acute ischemia-reperfusion via a mechanism involving Ca(2+)/calmodulin protein kinase II activation in association with upstream alteration in expression regulation of the sodium hydrogen exchanger-1.
From the Department of Cardiovascular Endocrinology, Hudson Institute of Medical Research, Clayton, Australia (L.A.B., J.M., E.K.F., A.J.R., M.J.Y.); and Department of Physiology, Melbourne University, Parkville, Australia (L.A.B., M.E.R., J.R.B., L.M.D.).
Laura A
LA
Bienvenu
From the Department of Cardiovascular Endocrinology, Hudson Institute of Medical Research, Clayton, Australia (L.A.B., J.M., E.K.F., A.J.R., M.J.Y.); and Department of Physiology, Melbourne University, Parkville, Australia (L.A.B., M.E.R., J.R.B., L.M.D.).
Melissa E
ME
Reichelt
From the Department of Cardiovascular Endocrinology, Hudson Institute of Medical Research, Clayton, Australia (L.A.B., J.M., E.K.F., A.J.R., M.J.Y.); and Department of Physiology, Melbourne University, Parkville, Australia (L.A.B., M.E.R., J.R.B., L.M.D.).
James
J
Morgan
From the Department of Cardiovascular Endocrinology, Hudson Institute of Medical Research, Clayton, Australia (L.A.B., J.M., E.K.F., A.J.R., M.J.Y.); and Department of Physiology, Melbourne University, Parkville, Australia (L.A.B., M.E.R., J.R.B., L.M.D.).
Elizabeth K
EK
Fletcher
From the Department of Cardiovascular Endocrinology, Hudson Institute of Medical Research, Clayton, Australia (L.A.B., J.M., E.K.F., A.J.R., M.J.Y.); and Department of Physiology, Melbourne University, Parkville, Australia (L.A.B., M.E.R., J.R.B., L.M.D.).
James R
JR
Bell
From the Department of Cardiovascular Endocrinology, Hudson Institute of Medical Research, Clayton, Australia (L.A.B., J.M., E.K.F., A.J.R., M.J.Y.); and Department of Physiology, Melbourne University, Parkville, Australia (L.A.B., M.E.R., J.R.B., L.M.D.).
Amanda J
AJ
Rickard
From the Department of Cardiovascular Endocrinology, Hudson Institute of Medical Research, Clayton, Australia (L.A.B., J.M., E.K.F., A.J.R., M.J.Y.); and Department of Physiology, Melbourne University, Parkville, Australia (L.A.B., M.E.R., J.R.B., L.M.D.).
Lea M
LM
Delbridge
From the Department of Cardiovascular Endocrinology, Hudson Institute of Medical Research, Clayton, Australia (L.A.B., J.M., E.K.F., A.J.R., M.J.Y.); and Department of Physiology, Melbourne University, Parkville, Australia (L.A.B., M.E.R., J.R.B., L.M.D.). morag.young@hudson.org.au.
Morag J
MJ
Young
D000818:Animals; D002118:Calcium / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006321:Heart / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology; D018161:Receptors, Mineralocorticoid / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020127:Recovery of Function / Q000502:physiology*; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology*; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology
D011960:Receptors, Estrogen; D018161:Receptors, Mineralocorticoid; D017923:Sodium-Hydrogen Exchangers; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
deoxycorticosterone; ischemia; mineralocorticoids; myocyte, cardiac; receptors, mineralocorticoid; reperfusion