Increased CaMKII activation and contrast changes of cardiac β1-and β3-Adrenergic signaling pathways in a humanized angiotensinogen model of hypertension

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