angiotensinogen and Hypercholesterolemia

Objective- AGT (Angiotensinogen) is the unique precursor of the renin-angiotensin system that is sequentially cleaved by renin and ACE (angiotensin-converting enzyme) to produce Ang II (angiotensin II). In this study, we determined how these renin-angiotensin components interact with megalin in kidney to promote atherosclerosis. Approach and Results- AGT, renin, ACE, and megalin were present in the renal proximal convoluted tubules of wild-type mice. Hepatocyte-specific AGT deficiency abolished AGT protein accumulation in proximal tubules and diminished Ang II concentrations in kidney, while renin was increased. Megalin was most abundant in kidney and exclusively present on the apical side of proximal tubules. Inhibition of megalin by antisense oligonucleotides (ASOs) led to ablation of AGT and renin proteins in proximal tubules, while leading to striking increases of urine AGT and renin concentrations, and 70% reduction of renal Ang II concentrations. However, plasma Ang II concentrations were unaffected. To determine whether AGT and megalin interaction contributes to atherosclerosis, we used both male and female low-density lipoprotein receptor

Topics: Angiotensin II; Angiotensinogen; Animals; Atherosclerosis; Female; Hypercholesterolemia; Low Density Lipoprotein Receptor-Related Protein-2; Male; Mice; Mice, Inbred C57BL; Oligonucleotides, Antisense; Renin-Angiotensin System

Hypercholesterolemia and hypertension are associated with aortic valve stenosis (AVS) in humans. We have examined aortic valve function, structure, and gene expression in hypercholesterolemic/hypertensive mice.. Control, hypertensive, hypercholesterolemic (Apoe(-/-)), and hypercholesterolemic/hypertensive mice were studied. Severe aortic stenosis (echocardiography) occurred only in hypercholesterolemic/hypertensive mice. There was minimal calcification of the aortic valve. Several structural changes were identified at the base of the valve. The intercusp raphe (or seam between leaflets) was longer in hypercholesterolemic/hypertensive mice than in other mice, and collagen fibers at the base of the leaflets were reoriented to form a mesh. In hypercholesterolemic/hypertensive mice, the cusps were asymmetrical, which may contribute to changes that produce AVS. RNA sequencing was used to identify molecular targets during the developmental phase of stenosis. Genes related to the structure of the valve were identified, which differentially expressed before fibrotic AVS developed. Both RNA and protein of a profibrotic molecule, plasminogen activator inhibitor 1, were increased greatly in hypercholesterolemic/hypertensive mice.. Hypercholesterolemic/hypertensive mice are the first model of fibrotic AVS. Hypercholesterolemic/hypertensive mice develop severe AVS in the absence of significant calcification, a feature that resembles AVS in children and some adults. Structural changes at the base of the valve leaflets include lengthening of the raphe, remodeling of collagen, and asymmetry of the leaflets. Genes were identified that may contribute to the development of fibrotic AVS.

Topics: Angiotensinogen; Animals; Aortic Valve; Aortic Valve Stenosis; Apolipoproteins E; Disease Models, Animal; Female; Fibrosis; Gene Expression Regulation; Hypercholesterolemia; Hypertension; Male; Mice, Inbred C57BL; Mice, Knockout; Plasminogen Activator Inhibitor 1; Renin; Severity of Illness Index

Atherosclerosis is an inflammatory disease resulting from interactions between various genetic and non-genetic factors. Angiotensinogen gene (AGT) belongs to polymorphic candidate genes. Recent evidence show that many traditional risk factors of coronary artery disease (CAD) influence synthesis of AGT. This report focuses on the interactions between M235T polymorphism of AGT gene and traditional risk factors of CAD.. 255 subjects, including 158 patients with angiographically confirmed CAD and 97 blood donors without history of cardiovascular diseases were studied. M235T polymorphism of the AGT gene was genotyped using PCR-RFLP method. To determine the possible interactions of AGT genotypes and traditional risk factors of CAD the attributable proportion due to interaction (AP) and synergy models were used.. The frequency of 235T allele carriers was significantly higher in patients than in controls (77.8 vs. 62.9, OR = 2.20, 95% CI; 1.10-4.40, P = 0.026, in multivariate logistic regression model). We found the existence of interaction between the 235T allele carrier-state and hypercholesterolemia (total cholesterol > or = 5 mmol/l) increasing the risk of CAD (SI = 3.39, 95% CI; 1.33-8.66, AP = 0.65, 95% CI; 0.39-0.91). The 235T allele also interacted with elevated LDL cholesterol levels (> or = 3 mmol/l) (AP = 0.49, 95% CI; 0.20-0.96), but not with the hypertension, overweight/ obesity and cigarette smoking.. The 235T allele increases the risk of CAD associated with the presence of hypercholesterolemia.

Topics: Adult; Angiotensinogen; Comorbidity; Coronary Artery Disease; Female; Genotype; Humans; Hypercholesterolemia; Logistic Models; Male; Middle Aged; Multivariate Analysis; Poland; Polymorphism, Genetic; Radiography; Risk Factors

Hypercholesterolemia-induced atherosclerosis is attenuated by either pharmacological antagonism of AT1 receptors or AT1A receptor deficiency. However, the mechanism underlying the pronounced responses to angiotensin II (Ang II) antagonism has not been determined. We hypothesized that hypercholesterolemia stimulates the production of angiotensin peptides to provide a rationale for the profound effect of AT1A receptor deficiency on atherogenesis.. Atherosclerotic lesions were analyzed in LDL receptor-deficient mice. Immunocytochemical analysis demonstrated that atherosclerotic lesions contained all the components of the conventional pathway for Ang II synthesis. AT1A receptor deficiency caused a marked decrease in atherosclerotic lesion size in both the aortic root and arch of male and female mice, without a discernible effect on composition. AT1A receptor deficiency-induced reductions in atherosclerosis were independent of systolic blood pressure and measurements of oxidation and chemoattractants. Aortic AT2 receptor mRNA expression was not altered in AT1A receptor-deficient mice, and AT2 receptor deficiency had no effect on lesion area or cellular composition. Hypercholesterolemia greatly augmented the systemic renin-angiotensin system, as demonstrated by large increases in plasma concentrations of angiotensinogen and angiotensin peptides (Ang II, III, IV, and 4-8). These increases were ablated in hypercholesterolemic AT1A receptor-deficient mice.. AT1A receptor deficiency had a striking effect in reducing hypercholesterolemia-induced atherosclerosis in LDL receptor-negative mice. Hypercholesterolemia was associated with increased systemic angiotensinogen and angiotensin peptides, which were reduced in AT1A receptor-deficient mice. These results demonstrate that hypercholesterolemia-induced stimulation of angiotensin peptide production provides a basis for the marked effect of AT1A receptor deficiency in reducing atherosclerosis.

Topics: Amino Acid Sequence; Angiotensin II; Angiotensin III; Angiotensinogen; Animals; Aortic Diseases; Arteriosclerosis; Chemokine CCL2; Chickens; Diet, Atherogenic; Female; Hypercholesterolemia; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, LDL; Renin-Angiotensin System; RNA, Messenger