Why the study?
The molecular mechanisms underlying declines in cardiac contractile function and beta-adrenergic receptor reserve in a novel humanized angiotensinogen model of hypertension were unclear.
CaMKIIδ overactivation and altered β-adrenergic receptor profiles contribute to cardiac contractile dysfunction in a humanized rat model of hypertension, which can be reversed by CaMKII inhibition.
CaMKIIδ hyperphosphorylation may contribute to β-AR dysfunction in hypertension; hypothesis-generating in this animal model, human validation needed.
Aims Upregulation of Ca 2+/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 ventricle (LV) myocyte CaMKIIδ and β 3 -AR are upregulated, but β 1 -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 β 1 -and β 3 -AR expressions and determined myocyte functional and [Ca 2+ ] I transient ([Ca 2+ ] 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 β 3 -AR protein levels and reduced β 1 -AR protein levels. CaMKIIδ phosphorylation (at Thr287), pCaMKIIδ was significantly increased by 35%. These changes were followed by significantly reduced basal cell contraction (dL/dt max ), relaxation (dR/dt max ) , and [Ca 2+ ] iT . Isoproterenol (10 −8 M) produced significantly smaller increases in dL/dt max , dR/dt max , and [Ca 2+ ] 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 [Ca 2+ ] iT . Significance LV myocyte CaMKIIδ overactivation with associated contrast changes in β 3 -AR and β 1 -AR may be the key molecular mechanism for the abnormal contractile phenotype and β-AR desensitization in this humanized model of hypertension.
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Sun et al. (2023) studied this question.
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