Abstract
Dexmedetomidine (DEX), a selective α2 adrenergic receptor (AR) agonist, is commonly used as a sedative drug during critical illness. In the present study, we explored a novel accelerative effect of DEX on cardiac fibroblast (CF) differentiation mediated by LPS and clarified its potential mechanism. LPS apparently increased the expression of α-SMA and collagen I/III and the phosphorylation of p38 and Smad-3 in the CFs of mice. These effects were significantly enhanced by DEX through increasing α2A-AR expression in CFs after LPS stimulation. The CFs from α2A-AR knockout mice were markedly less sensitive to DEX treatment than those of wild-type mice. Inhibition of protein kinase C (PKC) abolished the enhanced effects of DEX on LPS-induced differentiation of CFs. We also found that the α-SMA level in the second-passage CFs was much higher than that in the nonpassage and first-passage CFs. However, after LPS stimulation, the TNF-α released from the nonpassage CFs was much higher than that in the first- and second-passage CFs. DEX had no effect on LPS-induced release of TNF-α and IL-6 from CFs. Further investigation indicated that DEX promoted cardiac fibrosis and collagen I/III synthesis in mice exposed to LPS for four weeks. Our results demonstrated that DEX effectively accelerated LPS-induced differentiation of CFs to myofibroblasts through the PKC-p38-Smad2/3 signaling pathway by activating α2A-AR.
Highlights
Myocardial fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium and results in both systolic and diastolic dysfunctions [1].It is a common feature of advanced coronary heart disease, hypertension and cardiomyopathy, which results in an increased risk of morbidity and mortality [2,3]
LPS is a potent inducer of fibroblast-to-myofibroblast differentiation, which is characterized by the high expression of α-SMA [6]
To determine the effect of DEX on LPSinduced differentiation of cardiac fibroblast (CF) to myofibroblasts, the protein expression of α-SMA in the LPS-administered CFs with or without DEX treatment was first detected by immunofluorescence staining and western blot
Summary
Myocardial fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium and results in both systolic and diastolic dysfunctions [1]. It is a common feature of advanced coronary heart disease, hypertension and cardiomyopathy, which results in an increased risk of morbidity and mortality [2,3]. Clinical trials have demonstrated that 90-day mortality is increased in septic patients with DEX treatment [10]. The potential effect of DEX on LPS-induced cardiac fibrosis has not been well investigated
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