Altered Structure, Regulation, and Function of the Gene Encoding the Atrial Natriuretic Peptide in the Stroke-Prone Spontaneously Hypertensive Rat

Rubattu, Speranza; Lee‐Kirsch, Min Ae; DePaolis, P.; Giliberti, R.; Gigante, Bruna; Lombardi, Alessia; Volpe, Massimo; Lindpaintner, Klaus

doi:10.1161/01.res.85.10.900

Cited by 56 publications

(29 citation statements)

References 38 publications

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“…The gene encoding the atrial natriuretic peptide (ANP) was expressed at significantly lower levels in SHRSP compared with SHR (average difference was Ϫ3.2-fold across 2 independent probe sets). This is in agreement with earlier reports describing a threefold lower expression of ANP mRNA in the brain of SHRSP compared with SHR (17,24).…”

Section: Resultssupporting

confidence: 94%

Gene expression profiling and functional proteomic analysis reveal perturbed kinase-mediated signaling in genetic stroke susceptibility

Fornage¹,

Swank

Boerwinkle

et al. 2003

Physiological Genomics

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The stroke-prone spontaneously hypertensive rat (SHRSP) is a model of heritable hypertension-associated cerebrovascular injury. This study sought to compare SHRSP to the stroke-resistant SHR strain to identify genes and protein pathways whose expression and/or function was significantly altered between the strains prior to the onset of stroke. Cerebral cortex gene expression profiles from male SHRSPs and matched SHRs were examined by Affymetrix microarray analysis. mRNAs encoding the brain-derived neurotrophic factor receptor (TrkB) and multiple kinases of the MAPK/AKT signaling pathways, including JNK2, AKT2, and PI3K, were differentially expressed between SHRSP and SHR. Because these data suggest altered function in pathways involving MAP and AKT kinase activity, we performed Western blot using phosphorylation state-specific antibodies to characterize activity of MAP kinase and PI3K/AKT pathways. Changes in the levels of the phosphorylated forms of these kinases paralleled the changes in transcript levels observed between the strains. Two-dimensional gel electrophoresis and peptide fragment mass fingerprinting were used to identify altered protein substrates of these kinases. Protein profiling of kinase substrates further supported the notion of perturbed kinase-mediated signaling in SHRSP and identified adenylyl cyclase associated protein 2, TOAD-64, propionyl CoA carboxylase, APG-1, and valosin-containing protein as kinase targets whose phosphorylation state is altered between these strains. Altered gene and protein expression patterns in SHRSP are consistent with increased vulnerability of this strain to cerebrovascular injury.

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Section: Resultssupporting

confidence: 94%

Gene expression profiling and functional proteomic analysis reveal perturbed kinase-mediated signaling in genetic stroke susceptibility

Fornage¹,

Swank

Boerwinkle

et al. 2003

Physiological Genomics

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“…5,6,[21][22][23][24] Equal loading was checked by stripping and reprobing the membrane with troponin C. The following primary antibodies were used: ACE (BMA Biomedicals AG); ANP (Phoenix Pharmaceuticals Inc); angiotensin type 1 receptor (AT 1 R), ERK1/2, JNK, MKP1, p38-MAPK, phospho-JNK (Thr183/Tyr185), and troponin C (Santa Cruz Biotechnology Inc); and phospho-ERK1/2 (Thr202/Tyr204) and phospho-p-38 MAPK (Thr180/Tyr182) (New England Biolabs GmbH). Detection was performed with the enhanced chemiluminescence technique after incubation with a suitable secondary antibody coupled to horseradish peroxidase (ECL; Amersham Pharmacia Biotech).…”

Section: Immunoblot Analysismentioning

confidence: 99%

17β-Estradiol Attenuates the Development of Pressure-Overload Hypertrophy

et al. 2001

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Background-Cardiac hypertrophy is an independent risk factor for cardiovascular morbidity and mortality in men and in women. Epidemiological studies indicate that estrogen replacement therapy is cardioprotective; the mechanisms involved in this process, however, are poorly understood. We therefore studied the effect of 17␤-estradiol (E 2 ) on the development of pressure-overload hypertrophy. Methods and Results-Ovariectomized mice receiving E 2 or placebo underwent transverse aortic constriction (TAC) or sham operation. TAC led to a significant increase in ventricular mass compared with sham operation. E 2 treatment reduced cardiac hypertrophy by 31% and 26% compared with placebo 4 and 8 weeks after TAC, whereas it had no effect on the degree of pressure overload, as determined by hemodynamic measurements. Furthermore, E 2 blocked the increased phosphorylation of p38-mitogen-activated protein kinase (MAPK) observed in the placebo-treated animals with TAC. No differences were observed in the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 between the groups. E 2 had no effect on the expression of angiotensin-converting enzyme (ACE) or the angiotensin II type 1 receptor. Ventricular atrial natriuretic peptide (ANP) expression was detected only in the animals with TAC. Compared with placebo, E 2 treatment led to an increased expression of ANP in animals with pressure overload. Conclusions-Here, we show that E 2 attenuates the hypertrophic response to pressure overload in mice. This observation demonstrates that hormone replacement therapy with E 2 has direct effects on the heart and may be beneficial in the treatment of postmenopausal women to reduce cardiac hypertrophy. Key Words: hormones Ⅲ hypertrophy Ⅲ myocardium Ⅲ sex T he increase of left ventricular mass represents the structural mechanism of adaptation of the heart in response to pressure overload. The resulting left ventricular hypertrophy is an important negative predictor of cardiac morbidity and mortality and displays significant sex-based differences. 1,2 Estrogen is known to have multiple protective effects on the cardiovascular system. 3 The role of estrogen in the development of cardiac hypertrophy, however, is poorly understood. See p 1333We have shown previously that cardiac myocytes and cardiac fibroblasts contain both known estrogen receptor isoforms, called ␣ and ␤. 4 Via these receptors, estrogen can regulate the cardiac expression of endothelial and inducible NO synthase and connexin 43. 5 Estrogen also modulates the activity of the mitogen-activated protein kinase (MAPK) pathways in cardiac myocytes. 6 The MAPK signaling pathways consist of a sequence of successively acting kinases that ultimately result in the dual phosphorylation and activation of effector kinases such as p38-MAPKs, c-Jun N-terminal kinases (JNKs), and extracellular signal-regulated kinases (ERKs), which subsequently phosphorylate a large array of targets, leading to altered gene expression patterns. 7 These signalin...

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“…1,2 Among other genes, the atrial natriuretic peptide (ANP) gene has been involved in the pathogenesis of stroke. In fact, structural abnormalities of ANP are significantly associated with stroke in both an animal model, the stroke-prone spontaneously hypertensive rat, 3 and the North American white population of male physicians recruited in the Physicians Health Study (PHS). 4 Indeed, the ANP gene represents a candidate in vascular diseases.…”

mentioning

confidence: 99%

Atrial Natriuretic Peptide Gene Polymorphisms and Risk of Ischemic Stroke in Humans

Rubattu

Stanzione

Angelantonio

et al. 2004

Stroke

Self Cite

107

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Background and Purpose-A precise definition of genetic factors responsible for common forms of stroke is still lacking.The purpose of the present study was to investigate the contributory role of the genes encoding atrial natriuretic peptide (ANP) and type A natriuretic peptide receptor (NPRA) in humans' susceptibility to develop ischemic stroke. Methods-Allele and genotype frequencies of ANP and NPRA were characterized in an Italian case-control study with patients affected by vascular disease or risk factors. Subjects were recruited from the island of Sardinia (206 cases, 236 controls). Results-A significant association between the ANP/TC2238 polymorphic site and stroke occurrence was found when a recessive model of inheritance was assumed. The risk conferred by this mutant genotype, when estimated by multivariate logistic regression analysis, was 3.8 (95% confidence interval, 1.4 to 10.9). A significantly increased risk of stroke recurrence was observed among cases carrying the ANP/CC2238 genotype compared with cases carrying the ANP/TT2238 genotype (Pϭ0.04). No direct association of NPRA with stroke occurrence was detected. However, a significant epistatic interaction between the ANP/CC2238 genotype and an allelic variant of NPRA led to a 5.5-fold increased risk of stroke (95% confidence interval, 1.5 to 19.4). Conclusions-Our findings support a direct contributory role of ANP to stroke in humans. A significant interaction between ANP and NPRA on stroke occurrence was found.

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Altered Structure, Regulation, and Function of the Gene Encoding the Atrial Natriuretic Peptide in the Stroke-Prone Spontaneously Hypertensive Rat

Cited by 56 publications

References 38 publications

Gene expression profiling and functional proteomic analysis reveal perturbed kinase-mediated signaling in genetic stroke susceptibility

Gene expression profiling and functional proteomic analysis reveal perturbed kinase-mediated signaling in genetic stroke susceptibility

17β-Estradiol Attenuates the Development of Pressure-Overload Hypertrophy

Atrial Natriuretic Peptide Gene Polymorphisms and Risk of Ischemic Stroke in Humans

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