TY - JOUR
T1 - Angiotensin Receptor Blockade Improves Myocardial Beta-Adrenergic Receptor Signaling in Postinfarction Left Ventricular Remodeling
T2 - A Possible Link between Beta-Adrenergic Receptor Kinase-1 and Protein Kinase C Epsilon Isoform
AU - Takahashi, Toshiyuki
AU - Anzai, Toshihisa
AU - Yoshikawa, Tsutomu
AU - Maekawa, Yuichiro
AU - Mahara, Keitaro
AU - Iwata, Michikado
AU - Hammond, H. Kirk
AU - Ogawa, Satoshi
N1 - Funding Information:
This study was supported in part by grants 12770358 (to Dr. Anzai) and 13770364 (to Dr. Takahashi) from the Ministry of Education, Science, and Culture of Japan and by grants (to Dr. Anzai) from the Japan Heart Foundation, Takeda Science Foundation, and Keio University Medical Science Fund. Michael R. Bristow, MD, acted as Guest Editor for this paper.
PY - 2004/1/7
Y1 - 2004/1/7
N2 - OBJECTIVES: We tested the hypothesis that angiotensin II type 1 receptor blocker (ARB) may improve beta-adrenergic receptor (AR) coupling in heart failure (HF) after myocardial infarction (MI). BACKGROUND: Beta-AR desensitization is one of the mechanisms underlying the transition from compensated to decompensated HF. Beta-adrenergic receptor kinase-1 (ARK1), which can be induced by protein kinase C (PKC) in vitro, is activated in the failing myocardium, resulting in beta-AR uncoupling. METHODS: Models of MI in rats were produced by ligation of left coronary artery. Four weeks after surgery, they were randomized to vehicle (MI/control [C]) or candesartan (10 mg/kg/day) treatment (MI/ARB). Sham-operated rats, or shams, served as controls. RESULTS: After two weeks of treatment, echocardiography and hemodynamics showed that the left ventricular (LV) dimension increased and that the percent of fractional shortening and maximum rate of rise in left ventricular pressure (dP/dt) decreased in MI rats compared with shams. There were no differences in these indexes between MI/C and MI/ARB. An increase in maximum dP/dt under isoproterenol (ISO) stimulation was attenuated in MI/C but improved in MI/ARB. Reductions in the percentage of high-affinity sites of beta-AR and ISO-stimulated cyclic adenosine monophosphate production in noninfarcted myocardium were also improved by ARB treatment. Up-regulation of beta-ARK1 and PKC-epsilon isoform protein levels and activation of PKC in noninfarcted myocardium from MI/C were both inhibited by ARB treatment. CONCLUSIONS: Treatment with ARB during the chronic phase of MI improved beta-AR coupling in noninfarcted myocardium without affecting basal LV function. Cross-talk between beta-AR and angiotensin signaling through beta-ARK1 and PKC-epsilon may be responsible for the phenomenon.
AB - OBJECTIVES: We tested the hypothesis that angiotensin II type 1 receptor blocker (ARB) may improve beta-adrenergic receptor (AR) coupling in heart failure (HF) after myocardial infarction (MI). BACKGROUND: Beta-AR desensitization is one of the mechanisms underlying the transition from compensated to decompensated HF. Beta-adrenergic receptor kinase-1 (ARK1), which can be induced by protein kinase C (PKC) in vitro, is activated in the failing myocardium, resulting in beta-AR uncoupling. METHODS: Models of MI in rats were produced by ligation of left coronary artery. Four weeks after surgery, they were randomized to vehicle (MI/control [C]) or candesartan (10 mg/kg/day) treatment (MI/ARB). Sham-operated rats, or shams, served as controls. RESULTS: After two weeks of treatment, echocardiography and hemodynamics showed that the left ventricular (LV) dimension increased and that the percent of fractional shortening and maximum rate of rise in left ventricular pressure (dP/dt) decreased in MI rats compared with shams. There were no differences in these indexes between MI/C and MI/ARB. An increase in maximum dP/dt under isoproterenol (ISO) stimulation was attenuated in MI/C but improved in MI/ARB. Reductions in the percentage of high-affinity sites of beta-AR and ISO-stimulated cyclic adenosine monophosphate production in noninfarcted myocardium were also improved by ARB treatment. Up-regulation of beta-ARK1 and PKC-epsilon isoform protein levels and activation of PKC in noninfarcted myocardium from MI/C were both inhibited by ARB treatment. CONCLUSIONS: Treatment with ARB during the chronic phase of MI improved beta-AR coupling in noninfarcted myocardium without affecting basal LV function. Cross-talk between beta-AR and angiotensin signaling through beta-ARK1 and PKC-epsilon may be responsible for the phenomenon.
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U2 - 10.1016/j.jacc.2003.07.036
DO - 10.1016/j.jacc.2003.07.036
M3 - Article
C2 - 14715194
AN - SCOPUS:0345791411
SN - 0735-1097
VL - 43
SP - 125
EP - 132
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 1
ER -