Enhanced DNA synthesis in heart and kidney of newborn spontaneously hypertensive rats.

Walter, Susan V.; Hamet, Pavel

doi:10.1161/01.hyp.8.6.520

Cited by 56 publications

(28 citation statements)

References 22 publications

(16 reference statements)

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“…1,2 Enhanced DNA synthesis and organ hypertrophy before the elevation of blood pressure have been described in SHRs. 3 In addition, SHR-derived vascular smooth muscle cells (VSMCs) in culture show the exaggerated growth in comparison to cells from WKY rats. 4,5 We have previously shown that SHR-derived VSMCs produce angiotensin II (Ang II) in homogenous cultures.…”

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confidence: 99%

Complement 3 Is Involved in the Synthetic Phenotype and Exaggerated Growth of Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats

et al. 2004

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Abstract-Vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) show the synthetic phenotype and exaggerated growth in comparison with VSMCs from normotensive Wistar-Kyoto (WKY) rats. We investigated genes associated with the synthetic phenotype and exaggerated growth of VSMCs from SHR by microarray. Expression of 1300 transcripts was evaluated by microarray with total mRNA extracted from mid-layer aortic smooth muscle of 3-week-old SHR/Izumo and WKY/Izumo rats. mRNAs encoding sodium-dependent neurotransmitter transporter, epidermal growth factor precursor, EEF2, leptin receptor long-isoform b, clathrin assembly protein short form, and preprocomplement 3 (pre-pro-C3) were expressed only in aortic smooth muscle from SHR by microarray and by reverse-transcription polymerase chain reaction analysis. Pre-pro-C3 mRNA was detected only in cultured VSMCs from SHR. Exogenous C3 changed VSMCs to the synthetic phenotype. Antisense oligodeoxynucleotides (ODN) to C3 reduced the higher level of DNA synthesis in VSMCs from SHR. Antisense ODN to C3 increased expression of SM22␣ mRNA and decreased expression of osteopontin and matrix Gla mRNAs. It also decreased expression of growth factor mRNAs in VSMCs from SHR. In conclusion, we have shown that C3, independent of other complement molecules, has direct effects on the phenotype of VSMCs and stimulates growth of these cells. C3 is produced only by VSMCs from SHR. Therefore, C3 may be the gene underlying the synthetic phenotype and exaggerated growth of VSMCs from SHR. Key Words: hypertrophy Ⅲ remodeling Ⅲ rats Ⅲ muscle, smooth, vascular S pontaneously hypertensive rats (SHRs), an animal model of essential hypertension, show exaggerated growth of cardiovascular organs in comparison with normotensive Wistar-Kyoto (WKY) rats. 1,2 Enhanced DNA synthesis and organ hypertrophy before the elevation of blood pressure have been described in SHRs. 3 In addition, SHR-derived vascular smooth muscle cells (VSMCs) in culture show the exaggerated growth in comparison to cells from WKY rats. 4,5 We have previously shown that SHR-derived VSMCs produce angiotensin II (Ang II) in homogenous cultures. 6,7 We have reported that the mechanism underlying this enhanced generation of Ang II in VSMCs from SHRs appears to be the change from the contractile to the synthetic phenotype with increases in numbers of cytosolic organelles in comparison with VSMCs from WKY rats. 8 We hypothesized that genetic abnormalities are involved in the exaggerated growth and synthetic phenotype of VSMCs from SHRs. We investigated the responsible genes and found that the mRNA encoding complement 3 (C3) is expressed only in VSMCs from SHR and is associated with both the synthetic phenotype and exaggerated growth.

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confidence: 99%

Complement 3 Is Involved in the Synthetic Phenotype and Exaggerated Growth of Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats

et al. 2004

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“…3 Cardiac apoptosis has been documented during normal neonatal maturation, 4,5 aging, 6 hypertension, [7][8][9][10] ischemia, and failure. 11 The spontaneously hypertensive rat (SHR) is a model of genetically determined cardiac hypertrophy with increased cardiac mass and DNA content at birth, 12 further suggesting blood pressure-independent regulation. In this model, cardiac alterations evolve from concentric hypertrophy to dilated cardiomyopathy and heart failure.…”

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Apoptosis During Regression of Cardiac Hypertrophy in Spontaneously Hypertensive Rats

et al. 1999

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Abstract-We previously reported that increased apoptosis participates in the regression of aortic hypertrophy in spontaneously hypertensive rats. To further document the potential role of apoptosis in cardiovascular therapy, we examined apoptosis during regression of hypertrophy in the heart of spontaneously hypertensive rats receiving the antihypertensive drug enalapril (30 mg ⅐ kg) for 1 to 4 weeks, starting at 10 to 11 weeks of age. Systolic blood pressure and heart rate were measured by the tail-cuff method. Markers of apoptosis included oligonucleosomal DNA fragmentation in extracted cardiac DNA or in situ in ventricular cross sections labeled with terminal deoxynucleotidyl transferase. Cardiac DNA synthesis was evaluated by [ 3 H]-thymidine incorporation in vivo. All drugs reduced cardiac workload, defined as the product of blood pressure and heart rate, by Ͼ20% at 4 weeks. However, only nifedipine, enalapril, losartan, and propranolol reduced cardiac mass (Ͼ19%) within 4 weeks. Regression of cardiac hypertrophy was accompanied by a 50% to 300% increase in DNA fragmentation and a Ͼ20% reduction in DNA synthesis, resulting in a Ͼ20% reduction in cardiac DNA content after 4 weeks. Apoptosis induction occurred early and was transient within 4 weeks of nifedipine, enalapril, or losartan administration. With all regression-inducing drugs, the increase in DNA fragmentation occurred mainly in the subepicardium. Thus, transient induction of apoptosis in the subepicardium appears to be a characteristic feature of the early response to drug-induced regression of cardiac hypertrophy in spontaneously hypertensive rats. (Hypertension. 1999;34:229-235.)Key Words: ␤-adrenergic antagonist Ⅲ calcium channel blocker Ⅲ AT 1 antagonist Ⅲ ACE inhibitor A lthough cardiac hypertrophy is an independent risk factor for cardiovascular morbidity and mortality, the mechanisms regulating cardiac mass remain poorly defined. Different classes of antihypertensive drugs are not equally effective at reducing left ventricular mass, suggesting a blood pressure-independent regulation. 1 Cardiac hypertrophy involves both cellular hyperplasia (mainly in nonmyocytes) and hypertrophy (mainly in myocytes). 2 A potential mechanism contributing to the suppression of cardiac hypertrophy is the gene-regulated process of physiological cell self-destruction called apoptosis. 3 Cardiac apoptosis has been documented during normal neonatal maturation, 4,5 aging, 6 hypertension, 7-10 ischemia, and failure. 11 The spontaneously hypertensive rat (SHR) is a model of genetically determined cardiac hypertrophy with increased cardiac mass and DNA content at birth, 12 further suggesting blood pressure-independent regulation. In this model, cardiac alterations evolve from concentric hypertrophy to dilated cardiomyopathy and heart failure. 13 Results from our group suggest that neonatal cardiac hypertrophy in SHRs might be due in part to an imbalance between cell growth and apoptosis favoring DNA accumulation. 5 As the heart of untreated adult SHRs adapts to hyperte...

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“…The higher relative weights and protein contents found in aortas from newborn SHR may reflect a remodeling of this organ [14] . In addition, an adventitial remodeling in SHR was demonstrated by the increased proliferation and migration in AFs from SHR at the cytological level.…”

Section: Discussionmentioning

confidence: 94%

Dynamic expression of proteins associated with adventitial remodeling in adventitial fibroblasts from spontaneously hypertensive rats

et al. 2010

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Aim: To identify proteins that could potentially be involved in adventitial remodeling in vascular adventitial fibroblasts (AFs) from spontaneously hypertensive rats (SHR). Methods: AFs were isolated from thoracic aortas of 4-, 8-, 16-, and 24-week-old male SHR and Wistar-Kyoto (WKY) rats and cultured to passage 4. Proteomic differential expression profiles between SHR-AFs and WKY-AFs were investigated using 2-D electrophoresis (2-DE), whereas gel image analysis was processed using Image Master 2D Platinum. Protein spots were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Expression levels of annexin A1 in AFs and aortas from SHR and WKY rats were detected with Western blotting and immunofluorescence techniques. Results: In 4-, 8-, 16-, and 24-week-old SHR-AFs, 49, 59, 54, and 69 protein spots were found to have significant differences from the age-matched WKY-AFs. Fourteen spots with the same changes in patterns were analyzed in 4-, 8-, 16-, and 24-week-old SHR-AFs with mass spectrometry. Except for cytoskeleton proteins such as tubulin beta 5, it was found that annexin A1, translation elongation factor Tu, endoplasmic reticulum protein 29 and calcium-binding protein 1 were expressed in vascular AFs and their levels changed significantly in SHR-AFs compared with those in WKY-AFs. A decrease in annexin A1 in SHR-AFs was confirmed with Western blotting and immunofluorescence staining at the cell and tissue levels. Conclusion: The application of proteomic techniques revealed a number of novel proteins involved in adventitial remodeling of AFs from SHR, which provide new mechanisms responsible for the occurrence and development of hypertension and potential targets for influencing vascular remodeling in hypertension.

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Enhanced DNA synthesis in heart and kidney of newborn spontaneously hypertensive rats.

Cited by 56 publications

References 22 publications

Complement 3 Is Involved in the Synthetic Phenotype and Exaggerated Growth of Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats

Complement 3 Is Involved in the Synthetic Phenotype and Exaggerated Growth of Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats

Apoptosis During Regression of Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Dynamic expression of proteins associated with adventitial remodeling in adventitial fibroblasts from spontaneously hypertensive rats

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