Background: Atrial fibrosis is a feature of structural remodeling in atrial fibrillation (AF). Connective tissue growth factor (CTGF) is a potent profibrotic factor, but its role of CTGF in AF is not yet fully understood. Methods and Results:Right atrial appendages were obtained from 20 patients who underwent cardiac surgery (10 with sinus rhythm, 10 with AF). The mRNA level, protein level and immunohistochemical staining of CTGF were significantly increased in AF patients. In a porcine AF model, tissue angiotensin II (Ang II) and CTGF levels were significantly upregulated in both atria. In perfused rat hearts, Ang II stimulation increased CTGF expression, which could be inhibited by Ang II type I receptor antagonist. In a cell culture system, both atrial fibroblasts and myocytes were responsible for the increased CTGF expression under Ang II treatment. Ang II type I receptor antagonist could inhibit the Ang II-induced CTGF expression. Treating with recombinant CTGF, atrial fibroblasts expressed an increased level of collagen I. Furthermore, the CTGF level was highly correlated with tissue Ang II content in AF pigs.Conclusions: AF patients and animals exhibited a significantly increased expression of CTGF. Ang II stimulation upregulated CTGF expression in both atrial fibroblasts and myocytes. Ang II-induced CTGF expression might be involved in atrial substrate remodeling. (Circ J 2011; 75: 1592 - 1600

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BackgroundPlatelet activation is relevant to a variety of coronary heart diseases. Our previous studies revealed that sesamol possesses potent antiplatelet activity through increasing cyclic AMP formation. Although platelets are anucleated cells, they also express the transcription factor, NF-κB, that may exert non-genomic functions in platelet activation. Therefore, we further investigated the inhibitory roles of sesamol in NF-κB-mediated platelet function.MethodsPlatelet aggregation, Fura 2-AM fluorescence, and immunoblotting analysis were used in this study.ResultsNF-κB signaling events, including IKKβ phosphorylation, IκBα degradation, and p65 phosphorylation, were markedly activated by collagen (1 μg/ml) in washed human platelets, and these signaling events were attenuated by sesamol (2.5~25 μM). Furthermore, SQ22536 and ODQ, inhibitors of adenylate cyclase and guanylate cyclase, respectively, strongly reversed the sesamol (25 μM)-mediated inhibitory effects of IKKβ phosphorylation, IκBα degradation, and p65 phosphorylation stimulated by collagen. The protein kinase A (PKA) inhibitor, H89, also reversed sesamol-mediated inhibition of IκBα degradation. Moreover, BAY11-7082, an NF-κB inhibitor, abolished IκBα degradation, phospholipase C (PLC)γ2 phosphorylation, protein kinase C (PKC) activation, [Ca2+]i mobilization, and platelet aggregation stimulated by collagen. Preincubation of platelets with the inhibitors, SQ22536 and H89, both strongly reversed sesamol-mediated inhibition of platelet aggregation and [Ca2+]i mobilization.ConclusionsSesamol activates cAMP-PKA signaling, followed by inhibition of the NF-κB-PLC-PKC cascade, thereby leading to inhibition of [Ca2+]i mobilization and platelet aggregation. Because platelet activation is not only linked to hemostasis, but also has a relevant role in inflammation and metastasis, our data demonstrating that inhibition of NF-κB interferes with platelet function may have a great impact when these types of drugs are considered for the treatment of cancer and various inflammatory diseases.

A combination of low-dose rt-PA and TSD after embolic stroke reduced infarct volume, improved cerebral blood flow and provided neuroprotection and these effects were associated with reduction of apoptosis and attenuation of HIF-1α, TNF-α and iNOS expression. These results provide a positive contribution to better understand the therapeutic value of the combination of TSD with rt-PA in ischemic stroke and may support further clinical evaluation.