Angiotensin Receptor Blockade Improves Myocardial Beta-Adrenergic Receptor Signaling in Postinfarction Left Ventricular Remodeling: A Possible Link between Beta-Adrenergic Receptor Kinase-1 and Protein Kinase C Epsilon Isoform

Toshiyuki Takahashi, Toshihisa Anzai, Tsutomu Yoshikawa, Yuichiro Maekawa, Keitaro Mahara, Michikado Iwata, H. Kirk Hammond, Satoshi Ogawa

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Abstract

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.

Original languageEnglish
Pages (from-to)125-132
Number of pages8
JournalJournal of the American College of Cardiology
Volume43
Issue number1
DOIs
Publication statusPublished - 2004 Jan 7

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G-Protein-Coupled Receptor Kinase 2
Protein Kinase C-epsilon
Ventricular Remodeling
Angiotensin Receptors
Receptors, Adrenergic, beta
Protein Isoforms
Myocardial Infarction
Myocardium
Isoproterenol
Protein Kinase C
Heart Failure
Angiotensin II Type 1 Receptor Blockers
Angiotensins
Ventricular Pressure
Left Ventricular Function
Cyclic AMP
Ligation
Echocardiography

ASJC Scopus subject areas

  • Nursing(all)

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Angiotensin Receptor Blockade Improves Myocardial Beta-Adrenergic Receptor Signaling in Postinfarction Left Ventricular Remodeling : A Possible Link between Beta-Adrenergic Receptor Kinase-1 and Protein Kinase C Epsilon Isoform. / Takahashi, Toshiyuki; Anzai, Toshihisa; Yoshikawa, Tsutomu; Maekawa, Yuichiro; Mahara, Keitaro; Iwata, Michikado; Hammond, H. Kirk; Ogawa, Satoshi.

In: Journal of the American College of Cardiology, Vol. 43, No. 1, 07.01.2004, p. 125-132.

Research output: Contribution to journalArticle

Takahashi, Toshiyuki ; Anzai, Toshihisa ; Yoshikawa, Tsutomu ; Maekawa, Yuichiro ; Mahara, Keitaro ; Iwata, Michikado ; Hammond, H. Kirk ; Ogawa, Satoshi. / Angiotensin Receptor Blockade Improves Myocardial Beta-Adrenergic Receptor Signaling in Postinfarction Left Ventricular Remodeling : A Possible Link between Beta-Adrenergic Receptor Kinase-1 and Protein Kinase C Epsilon Isoform. In: Journal of the American College of Cardiology. 2004 ; Vol. 43, No. 1. pp. 125-132.
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abstract = "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.",
author = "Toshiyuki Takahashi and Toshihisa Anzai and Tsutomu Yoshikawa and Yuichiro Maekawa and Keitaro Mahara and Michikado Iwata and Hammond, {H. Kirk} and Satoshi Ogawa",
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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

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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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