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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

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

^* Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan
Departments of Medicine, Veterans Affairs Medical Center of San Diego and University of California, San Diego, California, USA

View larger version (17K): [in a new window]   Figure 1 Beta-adrenergic receptor responsiveness to isoproterenol (ISO) stimulation. In the basal condition, maximum rate of rise in left ventricular (LV) pressure (dP/dt) was lower in animals with myocardial infarction (MI) than in shams. An increase in dP/dt under ISO stimulation was attenuated in untreated MI animals (MI/control [C]) but improved in candesartan-treated animals (MI/angiotensin II type 1 receptor blocker [ARB]). *p < 0.05 MI/ARB vs. MI/C by repeated measures analysis of variance; n = 4 in each group.

View larger version (21K): [in a new window]   Figure 2 Beta-adrenergic receptor (AR) number (Bmax) and beta-AR/Gs coupling. (A) The beta-AR number was assessed by a radioligand binding study. The beta-AR number was not significantly different among the three groups. (B) A characteristic reduction in high-affinity binding, denoting uncoupling of beta-ARs, was noted in myocardial samples from noninfarcted regions of untreated myocardial infarction (MI) animals (MI/control [C]) compared with shams. Treatment of MI animals with candesartan (MI/angiotensin II type 1 receptor blocker [ARB]) increased the proportion of receptors exhibiting high-affinity agonist binding. *p < 0.001 MI/C vs. sham; p < 0.01 MI/ARB vs. MI/C; n = 6 in each group.

View larger version (22K): [in a new window]   Figure 3 Adenylyl cyclase activity. Basal 3',5'-cyclic adenosine monophosphate (cAMP) production of noninfarcted myocardium was not affected by heart failure after myocardial infarction (MI). Isoproterenol (ISO)-stimulated cAMP production was reduced in untreated MI animals (MI/control [C]) but increased in candesartan-treated animals (MI/angiotensin II type 1 receptor blocker [ARB]). On the other hand, cAMP production under stimulation by 5'-guanylylimidodiphosphate (Gpp[NH]p) and forskolin was not significantly different among the three groups. *p < 0.05 MI/C vs. sham; p < 0.05 MI/ARB vs. MI/C; n = 6 in each group.

View larger version (20K): [in a new window]   Figure 4 Activity of protein kinase C (PKC). Myocardial PKC activity in the particulate fraction was increased in noninfarcted viable myocardium of the untreated myocardial infarction (MI) animals (MI/control [C]) compared with shams. Treatment of MI animals with candesartan (MI/angiotensin II type 1 receptor blocker [ARB]) reduced PKC activity in the particulate fraction, compared with MI/C. *p < 0.05 MI/C vs. sham; p < 0.05 MI/ARB vs. MI/C; n = 5 in each group.

View larger version (27K): [in a new window]   Figure 5 Beta-adrenergic receptor kinase 1 (ARK1) and G-protein–coupled receptor kinase (GRK) 5 protein content. (A) Immunoblotting showed that the beta-ARK1 content in the particulate fraction was increased in noninfarcted viable myocardium of the untreated myocardial infarction (MI) animals (MI/control [C]) as compared with shams. Rats with MI treated with candesartan (MI/angiotensin II type 1 receptor blocker [ARB]) exhibited a reduction in beta-ARK1 protein level of noninfarcted viable myocardium, as compared with MI/C rats. (B) Immunoblotting showed that there was no significant difference in beta-ARK1 content in the supernatant fraction among the groups. (C) Representative immunoblots for GRK5 are shown. The GRK5 protein content in the particulate fraction did not change among the three groups. *p < 0.001 MI/C vs. sham; p < 0.01 MI/ARB vs. MI/C; n = 6 in each group.

View larger version (33K): [in a new window]   Figure 6 Protein content of protein kinase C (PKC)-epsilon. (A) Immunoblotting showed that the PKC-epsilon content in the particulate fraction was increased in noninfarcted viable myocardium of the untreated myocardial infarction (MI) animals (MI/control [C]) as compared with shams. Candesartan treatment of MI animals (MI/angiotensin II type 1 receptor blocker [ARB]) reduced the PKC-epsilon protein level in the particulate fraction, as compared with MI/C. (B) Immunoblotting showed that there was no significant difference in PKC-epsilon content in the supernatant fraction among the three groups. *p < 0.001 MI/C vs. sham; p < 0.001 MI/ARB vs. MI/C; n = 6 in each group.