angiotensinogen and Aortic-Valve-Stenosis

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

The progression of aortic stenosis (AS) has been shown to be faster in patients with the metabolic syndrome. We sought to determine the relationships between blood pressure, inflammation, oxidative stress and valvular inflammation in a population of normotensive and prehypertensive patients with AS.. In this study, 36 male patients (age: 61.5±2 years) with AS undergoing an aortic valve replacement were investigated. Plasma levels of adiponectin, oxidized-LDL (ox-LDL), angiotensinogen (AGN) and angiotensin I-II (Ang I-II) were measured. On explanted aortic valves, immunohistochemistry studies and quantitative PCR (q-PCR) analyses were performed to document the expression of inflammatory cytokines.. Systolic blood pressure (SBP) was positively correlated with plasma level of ox-LDL (r=0.4; p=0.02), AGN (r=0.41; p=0.01), and white blood cells count (r=0.33; p=0.04), whereas it was inversely related to plasma level of adiponectin (r=-.35; p=0.04). After adjustment for covariates, plasma level of ox-LDL (p=0.01) remained significantly associated with SBP (p=0.01). Within the aortic valve, expression of TNF-α was significantly associated with plasma levels of ox-LDL (r=0.58; p=0.03), Ang II (r=0.69; p=0.013), and waist circumference (r=0.60; p=0.02), whereas valvular expression of IL-6 was associated with plasma level of Ang II (r=0.51; p=0.03). In explanted AS valves, ox-LDL was documented near calcified areas and colocalized with Ang II, IL-6, and TNF-α.. Conditions associated with a higher oxidative stress and activation of the renin angiotensin system, such as encountered in viscerally obese and prehypertensive patients, contribute to higher valvular inflammation in AS.

Topics: Adiponectin; Angiotensin I; Angiotensin II; Angiotensinogen; Aortic Valve Stenosis; Biomarkers; Blood Pressure; Humans; Interleukin-6; Linear Models; Lipoproteins, LDL; Male; Middle Aged; Multivariate Analysis; Myocarditis; Oxidative Stress; Prehypertension; Renin-Angiotensin System; Tumor Necrosis Factor-alpha; Waist Circumference

The role of angiotensin II in pressure overload is still debated because notwithstanding its effects on myocyte contractility angiotensin II is not an obligatory factor for the development of hypertrophy. To define the role of angiotensin II in acute pressure overload we studied the effects of AT1 blockade (valsartan 80mg per day) on myocardial contractility, cardiac growth factor gene expression, and myocardial hypertrophy in aortic banded (60mmHg) pigs. Acute pressure overload caused an abrupt reduction of myocardial contractility, measured by the end-systolic stiffness constant, and a sharp increase in end-systolic stress which rapidly normalized (within 12h) in the placebo group. In AT1-blocked animals end-systolic stiffness constant remained significantly depressed up to 24h and end-systolic stress was still elevated up to 48h (both P<0.05 vs placebo). In both groups confocal microscopy revealed that granular staining of angiotensin II in cardiomyocyte cytoplasm disappeared after 30min of pressure overload. AT1 blockade abolished following cardiac overexpression of angiotensinogen and endothelin-1 genes as shown in RT-PCR studies and the consequent angiotensin II and endothelin-1 release in the coronary circulation. Conversely, insulin-like growth factor-I and ACE mRNA overexpression, as well as the onset of left ventricular mass increase, were not significantly affected by AT1 blockade.. (1) mechanical stress releases preformed angiotensin II from myocyte in vivo; (2) the AT1 blockade abolishes cardiac angiotensin II and endothelin-1 production with delayed recovery of myocardial contractility; whereas (3) the overexpression of insulin-like growth factor-I gene and the development of myocardial hypertrophy are not angiotensin II-mediated effects.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Aortic Valve Stenosis; Cardiac Catheterization; Cytoplasm; Disease Models, Animal; Endothelin-1; Gene Expression Regulation; Heart; Insulin-Like Growth Factor I; Microscopy, Confocal; Myocardium; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger; Stress, Mechanical; Swine; Systole; Tetrazoles; Valine; Valsartan