Abstractβ-Arrestins, which were originally characterized as terminators of heterotrimeric guanine nucleotidebinding protein (G protein)-coupled receptor (GPCR) signaling, also act as important signal transducers. An emerging concept in GPCR signaling is β-arrestin-biased agonism, in which specific ligand-activated GPCR conformational states selectively signal through β-arrestins, rather than through G proteins. Here, we show that mechanical stretch induced β-arrestin-biased signaling downstream of angiotensin II type I receptors (AT1Rs) in the absence of ligand or G protein activation. Mechanical stretch triggered an AT1R-mediated conformational change in β-arrestin similar to that induced by a β-arrestin-biased ligand to selectively stimulate receptor signaling in the absence of detectable G protein activation. Hearts from mice lacking β-arrestin or AT1Rs failed to induce responses to mechanical stretch, as shown by blunted extra-cellular signal-regulated kinase and Akt activation, impaired transactivation of the epidermal growth factor receptor, and enhanced myocyte apoptosis. These data show that the heart responds to acute increases in mechanical stress by activating β-arrestin-mediated cell survival signals.

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Agrawal DK. SOCS3 promotor hypermethylation and STAT3-NF-B interaction downregulate SOCS3 expression in human coronary artery smooth muscle cells. Am J Physiol Heart Circ Physiol 304: H776 -H785, 2013. First published January 18, 2013 doi:10.1152/ajpheart.00570.2012.-Suppressor of cytokine signaling-3 (SOCS3) is an intracellular negative regulator of cytokine signaling pathway. We recently found significant reduction in SOCS3 expression in coronary artery smooth muscle cells (CASMCs) of atherosclerotic swine and also in vitro cultured cells. Here, we investigated the underlying mechanisms of SOCS3 downregulation by IGF-1 and TNF-␣ in human CASMCs(hCASMCs). We propose that hypermethylation of CpG islands in the SOCS3 promoter is responsible for decrease in SOCS3 expression involving STAT3 and NFkB-p65 interaction. Western blot and qPCR data revealed significant upregulation of SOCS3 (6-to 10-fold) in hCASMC when treated individually with TNF-␣ (100 ng/ml) or IGF-1 (100 ng/ml). However, a significant decrease (5-fold) was observed by the combined treatment with TNF-␣ and IGF-1 compared with individual stimulation. IGF-1 phosphorylated STAT3 and TNF-␣-activated NF-B in hCASMCs. In the nuclear extract of hCASMCs stimulated with both TNF-␣ and IGF-1, there was an interaction between NF-B-p65 and pSTAT3, as determined by co-immunoprecipitation. Knockdown of STAT3 by small interfering RNA abolished SOCS3 expression in response to IGF-1. Methylation-specific PCR confirmed hypermethylation of SOCS3 promoter in hCASMCs stimulated with both TNF-␣ and IGF-1, and this was positively associated with elevated levels of DNA methyltransferase-I (9-to 10-fold). Knockdown of DNMT1 increased SOCS3 expression in IGF-1ϩTNF-␣-stimulated cells. Downregulation of SOCS3 in the presence of both TNF-␣ and IGF-1 in hCASMCs is due to SOCS3 promoter hypermethylation involving STAT3-NFkBp65 interaction. Because TNF-␣ and IGF-1 are released due to mechanical injury during coronary intervention, hypermethylation of SOCS3 gene could be an underlying mechanism of intimal hyperplasia and restenosis. cell signaling; cytokines; growth factors; hypermethylation; intimal hyperplasia; smooth muscle cells; suppressor of cytokine signaling 3; signal transducer and activator of transcription

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: The discovery of the immune checkpoint inhibitors such as programed cell death-1 protein/Programmed death ligand-1 or 2 and (PD-1/PD-L1 or PD-L2) and Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) paved the way for developing novel cancer treatment. The check point inhibitors are found to be very efficient in treating many hot tumors (with immune environment) such as bladder cancer, melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC) etc. Numerous clinical trials have been initiated to evaluate the safety and effectiveness of immune checkpoint inhibitors for patients with different cancer types, including hepatocellular carcinoma (HCC), pancreatic and prostate cancer. The results and findings of these trials are highly appreciated. However the search of check point inhibitors with better efficacy for the treatment of HCC is still going on. The present review focuses on advancement in HCC treatments with respect to various standard therapies and immunotherapy.