Wang Z.,Georgetown University |
Zeng C.,Chongqing Medical University |
Villar V.A.M.,Chongqing Institute of Cardiology |
Chen S.-Y.,University of Georgia |
And 12 more authors.
Hypertension | Year: 2016
The influence of a single gene on the pathogenesis of essential hypertension may be difficult to ascertain, unless the gene interacts with other genes that are germane to blood pressure regulation. G-protein-coupled receptor kinase type 4 (GRK4) is one such gene. We have reported that the expression of its variant hGRK4γ142V in mice results in hypertension because of impaired dopamine D1 receptor. Signaling through dopamine D1 receptor and angiotensin II type I receptor (AT1R) reciprocally modulates renal sodium excretion and blood pressure. Here, we demonstrate the ability of the hGRK4γ142V to increase the expression and activity of the AT1R. We show that hGRK4γ142V phosphorylates histone deacetylase type 1 and promotes its nuclear export to the cytoplasm, resulting in increased AT1R expression and greater pressor response to angiotensin II. AT1R blockade and the deletion of the Agtr1a gene normalize the hypertension in hGRK4γ142V mice. These findings illustrate the unique role of GRK4 by targeting receptors with opposite physiological activity for the same goal of maintaining blood pressure homeostasis, and thus making the GRK4 a relevant therapeutic target to control blood pressure. © 2015 American Heart Association, Inc. Source
Jia Y.,Merck And Co. |
Chen K.,Chongqing Institute of Cardiology |
Lin P.,Ohio State University |
Lieber G.,Merck And Co. |
And 19 more authors.
Nature Communications | Year: 2014
Injury to lung epithelial cells has a role in multiple lung diseases. We previously identified mitsugumin 53 (MG53) as a component of the cell membrane repair machinery in striated muscle cells. Here we show that MG53 also has a physiological role in the lung and may be used as a treatment in animal models of acute lung injury. Mice lacking MG53 show increased susceptibility to ischaemia-reperfusion and overventilation-induced injury to the lung when compared with wild-type mice. Extracellular application of recombinant human MG53 (rhMG53) protein protects cultured lung epithelial cells against anoxia/reoxygenation-induced injuries. Intravenous delivery or inhalation of rhMG53 reduces symptoms in rodent models of acute lung injury and emphysema. Repetitive administration of rhMG53 improves pulmonary structure associated with chronic lung injury in mice. Our data indicate a physiological function for MG53 in the lung and suggest that targeting membrane repair may be an effective means for treatment or prevention of lung diseases. © 2014 Macmillan Publishers Limited. Source
Zhang Y.,Chongqing Medical University |
Zhang Y.,Chongqing Institute of Cardiology |
Wang X.,Chongqing Medical University |
Wang X.,Chongqing Institute of Cardiology |
And 5 more authors.
Journal of Hypertension | Year: 2011
Objective: Abnormal vascular smooth muscle cell (VSMC) proliferation is involved in the development of vascular diseases. However, the mechanisms by which insulin exerts this effect are not completely known. We hypothesize that microRNAs might be involved in insulin-induced VSMC proliferation. Methods:VSMC proliferation was determined by [H]-thymidine incorporation; microRNAs were determined by microRNA chips and real-time PCR; and p21expression was determined by immunoblotting. Results: In this study, we found that insulin increased VSMC proliferation and miR-208 expression. Overexpression of miR-208 increased basal and insulin-mediated VSMC proliferation. Although a miR-208 inhibitor, by itself, had no effect on VSMC proliferation, it reduced the insulin-mediated cell proliferation. Moreover, miR-208 increased the transformation of cell cycle from G0/G1 phase to the S phase. Bioinformatics analysis found that p21, a member of the cyclin-dependent kinase (CDK)-inhibitory protein family, may be the target of miR-208. Insulin decreased p21 expression in VSMCs; transfection of miR-208 also decreased p21 protein expression. In the presence of miR-208 inhibitor, the inhibitory effect of insulin on p21 expression in VSMCs was partially blocked. The interaction between miR-208 and p21 was direct. Using a luciferase reporter with entire wild-type p21 3′UTR or a mutant p21 3′UTR in HEK293 cells, we found that miR-208 decreased but neither miR-208 mimic nor the mutant p21 3′UTR had any significant effect on the luciferase activity. Conclusion: This study indicates that miRNAs, miR-208, in particular, are involved in the insulin-induced VSMC proliferation via downregulation of its potential target, p21, a key member of CDK-inhibitory protein family. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source
Li C.,Chongqing Medical University |
Li C.,Chongqing Institute of Cardiology |
Pei F.,Chongqing Medical University |
Pei F.,Chongqing Institute of Cardiology |
And 5 more authors.
Clinical Biochemistry | Year: 2012
Coronary artery disease and acute myocardial infarction (AMI) are the leading causes of death for both men and women. Serum cardiac-specific troponin level is now used for the "early" diagnosis of AMI. However, due to the "delayed" release of troponin, an earlier, more sensitive and specific biomarker is urgently demanded to further reduce AMI mortality. Recent studies have found that circulating microRNAs (miRNAs) are closely linked to myocardial injury. Due to the cell-specific physiological functions and the stability of miRNAs in plasma, serum, and urine, they are emerging as sensitive biomarkers of AMI. This review summarizes the latest insights into the identification and potential application of plasma and serum miRNAs as novel biomarkers for diagnosis and prognosis of AMI. © 2012 The Canadian Society of Clinical Chemists. Source
Yang J.,Chongqing Medical University |
Yang J.,Chongqing Institute of Cardiology |
Chen C.,Chongqing Medical University |
Chen C.,Chongqing Institute of Cardiology |
And 12 more authors.
Journal of Hypertension | Year: 2012
Background: The renin-angiotensin (Ang) system controls blood pressure, in part, by regulating renal tubular sodium transport. In the kidney, activation of the angiotensin II type 1 (AT 1) receptor increases renal sodium reabsorption, whereas the angiotensin II type 2 (AT 2) receptor produces the opposite effect. We hypothesized that the AT 2 receptor regulates AT1 receptor expression and function in the kidney. METHODS AND Results: In immortalized renal proximal tubule (RPT) cells from Wistar-Kyoto rats, CGP42112, an AT 2 receptor agonist, decreased AT 1 receptor mRNA and protein expression (P < 0.05), as assessed by reverse transcriptase-polymerase chain reaction and immunoblotting. The inhibitory effect of the AT 2 receptor on AT 1 receptor expression was blocked by the AT 2 receptor antagonist, PD123319 (10 -6 mol/l), the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (10 -4 mol/l), or the nitric oxide-dependent soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (10 -5 mol/l), indicating that both nitric oxide and cyclic guanosine monophosphate (cGMP) were involved in the signaling pathway. Furthermore, CGP42112 decreased Sp1 serine phosphorylation and reduced the binding of Sp1 to AT 1 receptor DNA. Stimulation with Ang II (10 -11 mol/l per 30 min) enhanced Na-K-ATPase activity in RPT cells, which was prevented by pretreatment with CGP42112 (10 -7 mol/l per 24 h) (P < 0.05). The above-mentioned results were confirmed in RPT cells from AT 2 receptor knockout mice; AT 1 receptor expression and Ang II-stimulated Na +-K +-ATPase activity were greater in these cells than in RPT cells from wild-type mice (P < 0.05). AT 1/AT 2 receptors co-localized and co-immunoprecipitated in RPT cells; short-term CGP42112 (10 -7 mol/l per 30 min) treatment increased AT 1/AT 2 receptor co-immunoprecipitation (P < 0.05). Conclusions: These results indicate that the renal AT 2 receptor, via nitric oxide/cGMP/Sp1 pathway, regulates AT 1 receptor expression and function, which may be important in the regulation of sodium excretion and blood pressure. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source