Cardiopulmonary responses to chronic hypoxia in transgenic mice that overexpress ANP

Klinger, James R.; Petit, R; Curtin, Linda A.; Warburton, Rod R.; Wrenn, David S.; Steinhelper, Mark E.; Field, Loren J.; Hill, Nicholas S.

doi:10.1152/jappl.1993.75.1.198

Cited by 62 publications

(49 citation statements)

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“…The pressure increase is consistent with the expected pulmonary hypertension as a result of chronic hypoxia and is comparable to that reported in the literature. 7,12,24 The wild-type mice showed a significant overall increase in RV thickness of 44% in response to hypoxia, which is in good agreement with reports of RV weight change after similar hypoxia treatment. 1,12,29 RV thickening was substantially attenuated in ALPKO mice, however, and was even accompanied by a decrease in heart weight ( Table 1).…”

Section: Regional Hypertrophysupporting

confidence: 89%

“…7,12,24,26,29 For this study, 12 ALPKO mice and 16 wild-type mice of the same strain were randomly divided into two groups. Seven ALPKO and eight wild-type mice were housed in a normobaric environmental chamber for 4 weeks with an oxygen concentration of 11%.…”

Section: Hypoxia-induced Rv Hypertrophymentioning

confidence: 99%

“…7(A), p = 0.02], which confirms RV hypertrophy and is consistent with the typical RV weight increase seen after 3-4 weeks of hypoxia. 1,12,29 In this study, it was not feasible to weigh the ventricles separately, because we were interested in regional hypertrophy in the RV. Instead, the entire hearts were sectioned longitudinally in mice from the hypoxic (n = 6) and normoxic (n = 5) groups and stained for lacZ expression.…”

Section: Rv Wall Remodeling In Response To Hypoxiamentioning

confidence: 99%

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Deficiency of Actinin-Associated LIM Protein Alters Regional Right Ventricular Function and Hypertrophic Remodeling

2005

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Targeted deletion of actinin-associated LIM protein (ALP) in mice leads to right ventricular (RV) dysplasia and a mild RV cardiomyopathy. Although the phenotype has been thoroughly characterized, the mechanisms leading from the cytoskeletal defect to the disease are unclear. We hypothesized that ALP deficiency may be associated with (1) changes in regional systolic dysfunction and (2) regional dysregulation of hypertrophic growth, in accordance with the restricted expression of ALP in the outflow tract of the RV. We examined RV regional epicardial systolic strains with respect to end-diastole in ALP knockout (ALPKO) mice and wild-type controls using an open-chest preparation. Strain components were consistently lower in the ALPKO mice than wild-type controls (second principal strain E 2 : p = 0.05). RV pressure was slightly but not significantly lower in ALPKO mice as well. To assess regional growth, geometric remodeling was analyzed in ALPKO and wild-type mice after 4 weeks of chronic hypoxia (11% oxygen). The average amount of RV wall thickening in response to hypoxia was reduced to 11% in the ALPKO mice compared with 44% in the wild-type controls. In summary, the results are consistent with the view that disruption of ALP is associated with diminished RV contractile function as well as altered hypertrophic remodeling.

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Section: Regional Hypertrophysupporting

confidence: 89%

Section: Hypoxia-induced Rv Hypertrophymentioning

confidence: 99%

Section: Rv Wall Remodeling In Response To Hypoxiamentioning

confidence: 99%

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Deficiency of Actinin-Associated LIM Protein Alters Regional Right Ventricular Function and Hypertrophic Remodeling

2005

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“…5,8 -11 Transgenic mice overexpressing ANP have smaller hearts than do wild-type mice, and ANP gene delivery attenuates cardiac hypertrophy in spontaneously hypertensive rats. 5,7 Conversely, transgenic mice with homozygous disruption of the pro-ANP gene (Nppa -/-mice) or the natriuretic peptide receptor-A (NPR-A) gene (Npr1 -/-mice) exhibit cardiac hypertrophy at baseline that is out of proportion to the modest elevations in blood pressure (BP) observed in these models. 8 -11 Furthermore, in Npr1 -/-mice, pressure overload induced by transverse aortic constriction (TAC) results in a greater (55%) increase in left ventricular (LV) weight than in Npr1 ϩ/ϩ controls.…”

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confidence: 99%

Effects of Pressure Overload on Extracellular Matrix Expression in the Heart of the Atrial Natriuretic Peptide–Null Mouse

et al. 2003

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Abstract-This study tested the hypothesis that atrial natriuretic peptide has direct antihypertrophic actions on the heart by modulating expression of genes involved in cardiac hypertrophy and extracellular matrix production. Hearts of male, atrial natriuretic peptide-null and control wild-type mice that had been subjected to pressure overload after transverse aortic constriction and control unoperated hearts were weighed and subjected to microarray, Northern blot, and immunohistochemical analyses. Microarray and Northern blot analyses were used to identify genes that are regulated differentially in response to stress in the presence and absence of atrial natriuretic peptide. Immunohistochemical analysis was used to identify and localize expression of the protein products of these genes. Atrial natriuretic peptide-null mice demonstrated cardiac hypertrophy at baseline and an exaggerated hypertrophic response to transverse aortic constriction associated with increased expression of the extracellular matrix molecules periostin, osteopontin, collagen I and III, and thrombospondin, as well as the extracellular matrix regulatory proteins, matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-3, and the novel growth factor pleiotrophin compared with wild-type controls. These results support the hypothesis that atrial natriuretic peptide protects against pressure overload-induced cardiac hypertrophy and remodeling by negative modulation of genes involved in extracellular matrix deposition. Key Words: atrial natriuretic factor Ⅲ constriction Ⅲ aorta Ⅲ pressure overload Ⅲ hypertrophy, cardiac Ⅲ extracellular matrix Ⅲ growth substances A trial natriuretic peptide (ANP) inhibits cell growth and proliferation and induces apoptosis in a variety of cell types, including vascular smooth muscle cells (VSMCs) and cardiomyocytes. 1-3 Intracardiac ANP might also play an important autocrine/paracrine role in modulating cardiac remodeling under stress conditions and might protect against the development of pathologic cardiac hypertrophy. 4 -7 Synthesis and release of ANP in the heart are increased under stressful conditions such as pressure and volume overloadinduced pathologic cardiac hypertrophy, exercise-induced physiologic cardiac hypertrophy, heart failure, and hypoxic pulmonary hypertension. 1,2 Expression of ANP is inversely related to cardiac growth/hypertrophy. 5,8 -11 Transgenic mice overexpressing ANP have smaller hearts than do wild-type mice, and ANP gene delivery attenuates cardiac hypertrophy in spontaneously hypertensive rats. 5,7 Conversely, transgenic mice with homozygous disruption of the pro-ANP gene (Nppa -/-mice) or the natriuretic peptide receptor-A (NPR-A) gene (Npr1 -/-mice) exhibit cardiac hypertrophy at baseline that is out of proportion to the modest elevations in blood pressure (BP) observed in these models. 8 -11 Furthermore, in Npr1 -/-mice, pressure overload induced by transverse aortic constriction (TAC) results in a greater (55%) increase in left ventricular (LV) weight than in Np...

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“…Similarly, transgenic mice that overexpress ANP have reduced remodelling in chronic hypoxia (Klinger et al, 1993a). The mechanism by which ANP reduces the cardiopulmonary remodelling associated with chronic hypoxic pulmonary hypertension is undefined.…”

Section: Discussionmentioning

confidence: 99%

Neutral endopeptidase (NEP) inhibition in rats with established pulmonary hypertension secondary to chronic hypoxia

Thompson

Sheedy

Morice

1994

British J Pharmacology

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1Atrial natriuretic peptide (ANP) causes vasorelaxation in the pulmonary vasculature. ANP levels are elevated in conditions characterized by pulmonary hypertension and it has been hypothesized that ANP may be autoregulatory in the pulmonary circulation. 2 One route of ANP metabolism in vivo is by the action of the enzyme neutral endopeptidase (NEP). We have studied the effects of the NEP inhibitor, SCH 42495, in rats with established pulmonary hypertension secondary to chronic hypoxia. 3 Rats (n = 32) were divided into 4 groups. Normoxic controls were kept in air for 10 days (NClO) and all other animals were placed in a normobaric hypoxic chamber (Fi 02 10%). Chronic hypoxic controls were studied at 10 days (CHC10). After 10 days hypoxia the two remaining groups received oral treatment for a further 10 days, consisting of either SCH 42495 (30 mg kg-', twice daily CHT20) or methyl cellulose vehicle (0.4%, twice daily, CHV20). 4 Animals were anaesthetized and blood collected for measurement of plasma ANP. Hearts were dissected and ventricles weighed and the histology of the pulmonary vasculature examined. 5 CHClO rats had significant right ventricular hypertrophy (0.53 ± 0.08) and pulmonary vascular remodelling (29.0 0.01%) and had gained significantly less body weight (33.2 ± 5.5 g) than NC1O rats (0.31 ± 0.04, 10.9 0.01%, and 59.2 ± 11.9 g respectively). CHC1O rats had significantly elevated plasma ANP levels (58.4 ± 9.9 pM) compared with NClO rats (23.9 ± 32 pM). Treatment with SCH 42495 caused a significant reduction in pulmonary vascular remodelling (25.0 ± 0.01%) and right ventricular hypertrophy (0.52 ± 0.09) in CHT20 rats compared with CHV20 controls (33.0 ± 0.02% and 0.61 ± 0.09 respectively). Pulmonary vascular remodelling was also significantly lower in CHT20 rats than CHC1O animals. 6 Thus, short term inhibition of NEP causes regression of established pulmonary vascular remodelling and may be a useful therapeutic strategy in pulmonary hypertension.

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Cardiopulmonary responses to chronic hypoxia in transgenic mice that overexpress ANP

Cited by 62 publications

References 0 publications

Deficiency of Actinin-Associated LIM Protein Alters Regional Right Ventricular Function and Hypertrophic Remodeling

Deficiency of Actinin-Associated LIM Protein Alters Regional Right Ventricular Function and Hypertrophic Remodeling

Effects of Pressure Overload on Extracellular Matrix Expression in the Heart of the Atrial Natriuretic Peptide–Null Mouse

Neutral endopeptidase (NEP) inhibition in rats with established pulmonary hypertension secondary to chronic hypoxia

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