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

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.