title: Novel mechanism of blood pressure regulation by forkhead box class O1-mediated transcriptional control of hepatic angiotensinogen.
abstract: The renin-angiotensin system is a major determinant of blood pressure regulation. It consists of a cascade of enzymatic reactions involving 3 components: angiotensinogen, renin, and angiotensin-converting enzyme, which generate angiotensin II as a biologically active product. Angiotensinogen is largely produced in the liver, acting as a major determinant of the circulating renin-angiotensin system, which exerts acute hemodynamic effects on blood pressure regulation. How the expression of angiotensinogen is regulated is not completely understood. Here, we hypothesize that angiotensinogen is regulated by forkhead transcription factor forkhead box class O1 (Foxo1), an insulin-suppressed transcription factor, and thereby controls blood pressure in mice. We generated liver-specific Foxo1 knockout mice, which exhibited a reduction in plasma angiotensinogen and angiotensin II levels and a significant decrease in blood pressure. Using hepatocyte cultures, we demonstrated that overexpression of Foxo1 increased angiotensinogen expression, whereas hepatocytes lacking Foxo1 demonstrated a reduction of angiotensinogen gene expression and partially impaired insulin inhibition on angiotensinogen gene expression. Furthermore, mouse angiotensinogen prompter analysis demonstrated that the angiotensinogen promoter region contains a functional Foxo1-binding site, which is responsible for both Foxo1 stimulation and insulin suppression on the promoter activity. Together, these data demonstrate that Foxo1 regulates hepatic angiotensinogen gene expression and controls plasma angiotensinogen and angiotensin II levels, modulating blood pressure control in mice.
authors: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Balyor Scott & White Health, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.); and Central Texas Veterans Health Care System, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.).
authors: Yajuan
authors: Y
authors: Qi
authors: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Balyor Scott & White Health, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.); and Central Texas Veterans Health Care System, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.).
authors: Kebin
authors: K
authors: Zhang
authors: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Balyor Scott & White Health, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.); and Central Texas Veterans Health Care System, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.).
authors: Yuxin
authors: Y
authors: Wu
authors: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Balyor Scott & White Health, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.); and Central Texas Veterans Health Care System, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.).
authors: Zihui
authors: Z
authors: Xu
authors: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Balyor Scott & White Health, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.); and Central Texas Veterans Health Care System, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.).
authors: Qian Chen
authors: QC
authors: Yong
authors: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Balyor Scott & White Health, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.); and Central Texas Veterans Health Care System, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.).
authors: Rajesh
authors: R
authors: Kumar
authors: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Balyor Scott & White Health, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.); and Central Texas Veterans Health Care System, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.).
authors: Kenneth M
authors: KM
authors: Baker
authors: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Balyor Scott & White Health, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.); and Central Texas Veterans Health Care System, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.).
authors: Qinglei
authors: Q
authors: Zhu
authors: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Balyor Scott & White Health, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.); and Central Texas Veterans Health Care System, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.).
authors: Shouwen
authors: S
authors: Chen
authors: From the Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Balyor Scott & White Health, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.); and Central Texas Veterans Health Care System, Temple (Y.Q., K.Z., Y.W., Z.X., Q.C.Y., R.K., K.M.B., Q.Z., S.C., S.G.). sguo@medicine.tamhsc.edu.
authors: Shaodong
authors: S
authors: Guo
mesh_terms: D000804:Angiotensin II / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000808:Angiotensinogen / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D012084:Renin-Angiotensin System / Q000502:physiology
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D000808:Angiotensinogen; D000804:Angiotensin II
keywords: angiotensinogen; hypertension; liver