Effect of the angiotensinogen genotype on experimental hypertension in mice

Handtrack, Claudia; Cordasic, Nada; Klanke, Bernd; Veelken, Roland; Hilgers, Karl F.

doi:10.1007/s00109-007-0166-5

Cited by 10 publications

(8 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data differed from previous findings in regard to the slight increase in blood pressure levels induced by Aldo without Na ϩ excess in rats (34). The difference between our present observations and previous findings could be related to the fact that the mice were not uninephrectomized and the fact that C57BL6 mice seem to be resistant to hypertensive stimuli (7,26,32,33).…”

Section: Discussioncontrasting

confidence: 85%

A role for cardiotrophin-1 in myocardial remodeling induced by aldosterone

López‐Andrés

Martín-Fernández

Rossignol

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Hyperaldosteronim is associated with left ventricular (LV) hypertrophy (LVH) and fibrosis. Cardiotrophin (CT)-1 is a cytokine that induces myocardial remodeling. We investigated whether CT-1 mediates aldosterone (Aldo)-induced myocardial remodeling in two experimental models. Wistar rats were treated with Aldo-salt (1 mg·kg(-1)·day(-1)) with or without spironolactone (200 mg·kg(-1)·day(-1)) for 3 wk. Wild-type (WT) and CT-1-null mice were infused with Aldo (1 mg·kg(-1)·day(-1)) for 3 wk. Hemodynamic parameters were analyzed. LVH, fibrosis, inflammation, and CT-1 expression were evaluated in both experimental models by histopathological analysis, RT-PCR, Western blot analysis, and ELISA. Hypertensive Aldo-treated rats exhibited increased LV end-diastolic pressure and -dP/dt compared with controls. The cardiac index, LV cross-sectional area and wall thickness, cardiomyocyte size, collagen deposition, and inflammation were increased in Aldo-salt-treated rats. Myocardial expression of molecular markers assessing LVH and fibrosis as well as CT-l levels were also augmented by Aldo-salt. Spironolactone treatment reversed all the above effects. CT-1 correlated positively with hemodynamic, histological, and molecular parameters showing myocardial remodeling. In WT and CT-1-null mice, Aldo infusion did not modify blood pressure. Whereas Aldo treatment induced LVH, fibrosis, and inflammation in WT mice, the mineralocorticoid did not provoke cardiac remodeling in CT-1-null mice. In conclusion, in experimental hyperaldosteronism, the increase in CT-1 expression was associated with parameters showing LVH and fibrosis. CT-1-null mice were resistant to Aldo-induced LVH and fibrosis. These data suggest a key role for CT-1 in cardiac remodeling induced by Aldo independent of changes in blood pressure levels.

show abstract

Section: Discussioncontrasting

confidence: 85%

A role for cardiotrophin-1 in myocardial remodeling induced by aldosterone

López‐Andrés

Martín-Fernández

Rossignol

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Handtrack et al. 20 subjected genetically modified mice harbouring between one and four copies of the angiotensinogen gene to high‐renin (2K1C) renovascular hypertension or to low‐renin (DOCA salt) mineralocorticoid hypertension. Interestingly, the degree of the 2K1C hypertension was not affected by the angiotensinogen genotype, whereas there was a marked gene effect on BP in DOCA‐hypertensive animals.…”

Section: Discussionmentioning

confidence: 99%

Ace gene dosage influences the development of renovascular hypertension

Ceroni

Moreira

Mostarda

et al. 2010

Clin Exp Pharma Physio

View full text Add to dashboard Cite

1. Clinical and experimental evidence highlights the importance of the renin-angiotensin system in renovascular hypertension. Furthermore, genetic factors affecting angiotensin-converting enzyme (ACE) could influence the development of renovascular hypertension. 2. To test the effect of small gene perturbations on the development of renovascular hypertension, mice harbouring two or three copies of the Ace gene were submitted to 4 weeks of two-kidney, one-clip (2K1C) hypertension. Blood pressure (BP), cardiac hypertrophy, baroreflex sensitivity and blood pressure and heart rate variability were assessed and compared between the different groups. 3. The increase in BP induced by 2K1C was higher in mice with three copies of the Ace gene compared with mice with only two copies (46 vs 23 mmHg, respectively). Moreover, there was a 3.8-fold increase in the slope of the left ventricle mass/BP relationship in mice with three copies of the Ace gene. Micewith three copies of the Ace gene exhibited greater increases in cardiac and serum ACE activity than mice with only two copies of the gene. Both baroreflex bradycardia and tachycardia were significantly depressed in mice with three copies of the Ace gene after induction of 2K1C hypertension. The variance in basal systolic BP was greater in mice with three copies of the Ace gene after 2K1C hypertension compared with those with only two copies of the gene (106 vs 54%, respectively). In addition, the low-frequency component of the pulse interval was higher mice with three copies of the Ace gene after 2K1C hypertension compared with those with only two (168 vs 86%, respectively). Finally, in mice with three copies of the Ace gene, renovascular hypertension induced a 6.1-fold increase in the sympathovagal balance compared with a 3.2-fold increase in mice with only two copies of the gene. 4. Collectively, these data provide direct evidence that small genetic disturbances in ACE levels per se have an influence on haemodynamic, cardiac mass and autonomic nervous system responses in mice under pathological perturbation.

show abstract

“…Although this may reflect the fact that C57Bl6 mice are less susceptible to hypertension than some other strains, eg, 129/sv mice, 43,44 the data are consistent with previous mouse studies using DOC pellets over 6 to 8 weeks. 24,25 Vascular inflammation, however, does not necessarily result in elevated blood pressure; eg, overexpression of endothelin 1 in endothelial cells is characterized by increased vascular inflammation but not by increased SBP. 45 Although the MR-mediated inflammatory response appears to be involved in the genesis of the hypertension seen in this model, numerous studies have shown that cardiac fibrosis in the DOC/salt model is not secondary to hypertension.…”

Section: Macrophages and Sbp: Regulation By Inflammatory Cellsmentioning

confidence: 99%

“…Mice of each genotype were randomly assigned to one of the following treatments, resulting in a total of 4 groups of mice for each time point: (1) control treatment for 8 days, (2) continuous DOC treatment for 8 days and control treatment for 8 weeks, and (3) continuous DOC treatment for 8 weeks. 24,25 Mice receiving DOC treatment received an SC 7-mg, 21-day release pellet that was replaced every 3 weeks. …”

mentioning

confidence: 99%

Deletion of Mineralocorticoid Receptors From Macrophages Protects Against Deoxycorticosterone/Salt-Induced Cardiac Fibrosis and Increased Blood Pressure

et al. 2009

View full text Add to dashboard Cite

Abstract-Increased mineralocorticoid levels plus high salt promote vascular inflammation and cardiac tissue remodeling.Mineralocorticoid receptors are expressed in many cell types of the cardiovascular system, including monocytes/macrophages and other inflammatory cell types. Although mineralocorticoid receptors are expressed in monocytes/macrophages, their role in regulating macrophage function to date has not been investigated. We, thus, used the Cre/LoxP-recombination system to selectively delete mineralocorticoid receptors from monocytes/macrophages with the lysozyme M promoter used to drive Cre expression (MR flox/flox /LysM Cre/Ϫ mice). Male mice from each genotype (MR flox/flox or wild-type and MR flox/flox /LysM Cre/Ϫ mice) were uninephrectomized, given 0.9% NaCl solution to drink, and treated for 8 days or 8 weeks with either vehicle (nϭ10) or deoxycorticosterone (nϭ10). Equivalent tissue macrophage numbers were seen for deoxycorticosterone treatment of each genotype at 8 days; in contrast, plasminogen activator inhibitor type 1 and NAD(P)H oxidase subunit 2 levels were increased in wild-type but not in MR flox/flox / LysM Cre/Ϫ mice given deoxycorticosterone. Baseline expression of other inflammatory genes was reduced in MR flox/flox /LysM Cre/Ϫ mice compared with wild-type mice. At 8 weeks, deoxycorticosterone-induced macrophage recruitment and connective tissue growth factor and plasminogen activator inhibitor type 1 mRNA levels were similar for each genotype; in contrast, MR flox/flox /LysMCre/Ϫ mice showed no increase in cardiac fibrosis or blood pressure, as was seen in wild-type mice at 8 weeks. These data demonstrate the following points: (1) mineralocorticoid receptor signaling regulates basal monocyte/macrophage function; (2) macrophage recruitment is not altered by loss of mineralocorticoid receptor signaling in these cells; and (3) a novel and significant role is seen for macrophage signaling in the regulation of cardiac remodeling and systolic blood pressure in the deoxycorticosterone/salt model. T he clinical use of mineralocorticoid receptor (MR) antagonists added to the current standard of care reduces morbidity and mortality in patients with congestive heart failure 1,2 and reduces blood pressure and proteinuria as monotherapy in essential hypertension. 3 Although the precise mechanism for this protection remains to be determined, considerable insights have been obtained from experimental models of mineralocorticoid/salt-mediated cardiac fibrosis 4 -6 ; hypertension, cardiac hypertrophy, and fibrosis are key responses to the administration of aldosterone or deoxycorticosterone (DOC) concurrently with a high salt intake for 8 weeks. Importantly, the pathogenesis of cardiac fibrosis is independent of hypertension and cardiac hypertrophy in this model, suggesting a direct role for MR activation in driving the onset and progression of cardiovascular disease. 4 -6 We and others have previously identified vascular inflammation (ie, osteopontin and plasminogen activator inhibitor type 1 [PA...

show abstract

Effect of the angiotensinogen genotype on experimental hypertension in mice

Cited by 10 publications

References 35 publications

A role for cardiotrophin-1 in myocardial remodeling induced by aldosterone

A role for cardiotrophin-1 in myocardial remodeling induced by aldosterone

Ace gene dosage influences the development of renovascular hypertension

Deletion of Mineralocorticoid Receptors From Macrophages Protects Against Deoxycorticosterone/Salt-Induced Cardiac Fibrosis and Increased Blood Pressure

Contact Info

Product

Resources

About