Increased β-adrenergic stimulation augments vascular smooth muscle cell calcification via PKA/CREB signalling

Abstract

In chronic kidney disease (CKD), hyperphosphatemia promotes medial vascular calcification, a process augmented by osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). VSMC function is regulated by sympathetic innervation, and these cells express α- and β-adrenergic receptors. The present study explored the effects of β2-adrenergic stimulation by isoproterenol on VSMC calcification. Experiments were performed in primary human aortic VSMCs treated with isoproterenol during control or high phosphate conditions. As a result, isoproterenol dose dependently up-regulated the expression of osteogenic markers core-binding factor α-1 (CBFA1) and tissue-nonspecific alkaline phosphatase (ALPL) in VSMCs. Furthermore, prolonged isoproterenol exposure augmented phosphate-induced calcification of VSMCs. Isoproterenol increased the activation of PKA and CREB, while knockdown of the PKA catalytic subunit α (PRKACA) or of CREB1 genes was able to suppress the pro-calcific effects of isoproterenol in VSMCs. β2-adrenergic receptor silencing or inhibition with the selective antagonist ICI 118,551 blocked isoproterenol-induced osteogenic signalling in VSMCs. The present observations imply a pro-calcific effect of β2-adrenergic overstimulation in VSMCs, which is mediated, at least partly, by PKA/CREB signalling. These observations may support a link between sympathetic overactivity in CKD and vascular calcification.

The Associations Between Abdominal Obesity and Coronary Artery Calcification in Chronic Kidney Disease Population

“…Moreover, in hyperphosphatemia, vascular smooth muscle cells tend to differentiate into a synthetic phenotype, promoting calcification within the medial wall. 14,16,[29][30][31] The binding of osteocalcin to hydroxyapatite further contributes to hydroxyapatite deposition and subsequent calcification. 32,33 Previous studies have suggested a relationship between CKD and the CAC severity.…”

Periostin Augments Vascular Smooth Muscle Cell Calcification via β-Catenin Signaling

“…The HAoSMCs were treated with equal amounts of the vehicle as a control. HAoSMCs were transfected with 10 nM POSTN (ID: s20888) or negative control (ID: 4390843) siRNA using a siPORT amine transfection reagent (all from Fisher Scientific, Vienna, Austria) [ 33 ]. For the calcification experiments, the HAoSMCs were treated for 11 days with 10 mM β-glycerophosphate and 1.5 mM CaCl 2 (Sigma Aldrich, Vienna, Austria) as a calcification medium [ 34 ].…”

Nutritional assessment models for Alzheimer's disease: Advances and perspectives

“…The mice were injected with colchicine, a microtubule disrupting agent, on each side of the hippocampus, and its learning and memory ability decreases obviously, the pathological examination showed colchicine selective destruction of particle vertebral body cell nucleus, hippocampus neurons induced deformation of fiber, choline acetyltransferase fell, the morphology of neurons apoptosis characteristics, similar to the AD pathology performance. Isoproterenol can activate PKA, after the bilateral hippocampus of rats is injected with isoproterenol, the symptoms of Tau protein hyperphosphorylation will appear, and memory impairment and the level of oxidative stress will increase after 48 h (Moser et al., 2021). Other drugs, such as O‐GlcNAcylation and haloperidol, can be used as inducers to induce Tau hyperphosphorylation (Huang et al., 2020; Koppel et al., 2016).…”