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Aims: Upregulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) contributes to the pathogenesis of cardiovascular disease, including hypertension. Transgenic rats expressing the human angiotensinogen gene [TGR (hAGT)L1623] are a new novel humanized model of hypertension that associates with declines in cardiac contractile function and β-adrenergic receptor (AR) reserve. The molecular mechanisms are unclear. We tested the hypothesis that in TGR (hAGT)L1623 rats, left ventricular (LV) myocyte CaMKIIδ and β3-AR are upregulated, but β1-AR is down-regulated, which are important causes of cardiac dysfunction and β-AR desensitization. Main methods: We compared LV myocyte CaMKIIδ, CaMKIIδ phosphorylation (at Thr287) (pCaMKIIδ), and β1-and β3-AR expressions and determined myocyte functional and [Ca2+]I transient ([Ca2+]iT) responses to β-AR stimulation with and without pretreatment of myocytes using an inhibitor of CaMKII, KN-93 (10−6 M, 30 min) in male Sprague Dawley (SD; N = 10) control and TGR (hAGT)L1623 (N = 10) adult rats. Key findings: Hypertension in TGR (hAGT)L1623 rats was accompanied by significantly increased LV myocyte β3-AR protein levels and reduced β1-AR protein levels. CaMKIIδ phosphorylation (at Thr287), pCaMKIIδ was significantly increased by 35%. These changes were followed by significantly reduced basal cell contraction (dL/dtmax), relaxation (dR/dtmax), and [Ca2+]iT. Isoproterenol (10−8 M) produced significantly smaller increases in dL/dtmax, dR/dtmax, and [Ca2+]iT. Moreover, only in TGR (hAGT)L1623 rats, pretreatment of LV myocytes with KN-93 (10−6 M, 30 min) fully restored normal basal and isoproterenol-stimulated myocyte contraction, relaxation, and [Ca2+]iT. Significance: LV myocyte CaMKIIδ overactivation with associated contrast changes in β3-AR and β1-AR may be the key molecular mechanism for the abnormal contractile phenotype and β-AR desensitization in this humanized model of hypertension. |
