Novel Mechanism of Blood Pressure Regulation By Forkhead Box Class O1–Mediated Transcriptional Control of Hepatic Angiotensinogen

Abstract

The renin-angiotensin system (RAS) is a major determinant of blood pressure regulation. It consists of a cascade of enzymatic reactions involving three components: angiotensinogen (Agt), renin, and angiotensin-converting enzyme (ACE), which generate angiotensin II (Ang II) as a biologically active product. Agt is largely produced in the liver, acting as a major determinant of the circulating RAS, which exerts acute hemodynamic effects on blood pressure regulation. How the expression of Agt is regulated is not completely understood. Here we hypothesize that Agt 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 (L-F1KO mice), which exhibited a reduction in plasma Agt and Ang II levels and a significant decrease in blood pressure. Using hepatocyte cultures, we demonstrated that overexpression of Foxo1 increased Agt expression, while hepatocytes lacking Foxo1 demonstrated a reduction of Agt gene expression and partially impaired insulin inhibition on Agt gene expression. Furthermore, mouse Agt prompter analysis demonstrated that the Agt 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 Agt gene expression and controls plasma Agt and Ang II levels, modulating blood pressure control in mice.

Activation of Foxo1 by Insulin Resistance Promotes Cardiac Dysfunction and β–Myosin Heavy Chain Gene Expression

“…For example, we recently identified angiotensinogen as a Foxo1 target gene, which stimulates angiotensin II generation controlling blood pressure and cellular apoptosis. 12,25 Finally, Foxo1 activation is involved in metabolic remodeling. It has been shown recently that cardiac inactivation of Foxo1 in HFD mice promotes animal survival by protecting cardiac function, 20 in which a major mechanism is that Foxo1 inactivation enhances myocardial glucose utilization via increasing glucokinase gene expression.…”

“…23,25 Immunoprecipitated DNA was analyzed by polymerase chain reaction with primers specific to the promoters of the β-MHC gene: 5′-ACCATCTGACATTCTACAGTCT-3′ and 5′-AGAGCTCATCCTTTCTGGTCAT-3′.…”

Angiotensin AT1A receptors on leptin receptor–expressing cells control resting metabolism

“…Further, administration of leptin to ob/ob mice enhances plasma RAS expression (37,38), and angiotensinogen is expressed in AgRP neurons of the ARC (21). Leptin-activated second-messenger pathways, such as p-STAT3, have also been shown to promote the transcription of angiotensinogen in other cell types (39)(40)(41)(42)(43)(44). In addition, i.c.v.…”

Resistance exercise training increase activation of AKT-eNOS and Ref-1 expression by FOXO-1 activation in aorta of F344 rats

“…In a hepatocytic FOXO1 knockout rat model, blood pressure was significantly decreased by the inhibition of angiotensinogen compared with wild type mice [36]. Activated FOXOs suppress angiogenesis in endothelial cells and inhibit excessive growth in cardiomyocytes [22].…”