Expression of Proto-oncogenes and Gene Mutation of Sarcomeric Proteins in Patients With Hypertrophic Cardiomyopathy

Kai, Hisashi; Muraishi, A; Sugiu, Yuji; Nishi, Hiromi; Seki, Yukihiko; Kuwahara, Fumitaka; Kimura, Akinori; Kato, Hirohisa; Imaizumi, Tsutomu

doi:10.1161/01.res.83.6.594

Cited by 84 publications

(62 citation statements)

References 43 publications

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“…A recent study has shown that enhanced expression of several cellular genes associated with cell size control has been found in HCM patients. Interestingly, cardiomyocyte size was found to be correlated with the expression level of c-H-ras and cMyc [177], suggesting that c-H-ras and c-Myc may play a role in the hypertrophic mechanism in HCM by increasing cardiomyocyte size. This conclusion was further supported by another experiment in which overexpression of ras in cardiomyocytes induces enlarged cardiomyocyte size and cardiac hypertrophy [136].…”

Section: Organ Hypertrophy or Atrophymentioning

confidence: 98%

Molecular mechanism of size control in development and human diseases

Yang

2011

Cell Res

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How multicellular organisms control their size is a fundamental question that fascinated generations of biologists. In the past 10 years, tremendous progress has been made toward our understanding of the molecular mechanism underlying size control. Original studies from Drosophila showed that in addition to extrinsic nutritional and hormonal cues, intrinsic mechanisms also play important roles in the control of organ size during development. Several novel signaling pathways such as insulin and Hippo-LATS signaling pathways have been identified that control organ size by regulating cell size and/or cell number through modulation of cell growth, cell division, and cell death. Later studies using mammalian cell and mouse models also demonstrated that the signaling pathways identified in flies are also conserved in mammals. Significantly, recent studies showed that dysregulation of size control plays important roles in the development of many human diseases such as cancer, diabetes, and hypertrophy.

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Section: Organ Hypertrophy or Atrophymentioning

confidence: 98%

Molecular mechanism of size control in development and human diseases

Yang

2011

Cell Res

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“…In three independent hematoxylin-eosin-stained sections, the shortest transverse myocyte diameter was measured in 50 nucleated transverse sections of the myocytes in each rat. 17 The percent area of myocardial fibrosis was evaluated in three independent Mallory-Azan-stained sections of each rat. 18 Immunohistostaining for monocytes/macrophages was performed using an antibody against ED1 (Chemicon International, Temecula, CA, USA) and a commercially available detection system (DAKO, Glostrup, Denmark).…”

Section: Morphometry and Immunohistostainingmentioning

confidence: 99%

Enhanced cardiac inflammation and fibrosis in ovariectomized hypertensive rats: a possible mechanism of diastolic dysfunction in postmenopausal women

et al. 2011

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Diastolic dysfunction is more prevalent in individuals with hypertension, particularly postmenopausal women; however, the pathogenesis of diastolic dysfunction remains unknown. Pressure overload activates cardiac inflammation, which induces myocardial fibrosis and diastolic dysfunction in rats with a suprarenal aortic constriction (AC). Therefore, we examined the effects of bilateral ovariectomy (OVX) on left ventricle (LV) remodeling, diastolic dysfunction and cardiac inflammation in hypertensive female rats. Rats were randomized to OVX+AC, OVX and AC groups as well as a Control group receiving sham operations for both the procedures. Rats underwent OVX at 6 weeks and AC at 10 weeks (Day 0). At Day 28, OVX did not appear to affect arterial pressure, cardiac hypertrophy or LV fractional shortening in AC rats. However, OVX increased myocardial fibrosis, elevated LV end-diastolic pressure and reduced the transmitral Doppler spectra early to late filling velocity ratio in AC rats. AC-induced transient myocardial monocyte chemoattractant protein-1 expression and macrophage infiltration, both of which peaked at Day 3 and were augmented and prolonged by OVX. At Day 28, dihydroethidium staining revealed superoxide generation in the intramyocardial arterioles in the OVX+AC group but not in the AC group. NOX1, a functional subunit of nicotinamide adenine dinucleotide phosphate oxidase, was upregulated only in the OVX+AC group at Day 28. Chronic 17b-estradiol replacement prevented the increases in macrophage infiltration, NOX1 upregulation, myocardial fibrosis and diastolic dysfunction in OVX+AC rats. In conclusion, we suggest that estrogen deficiency augments cardiac inflammation and oxidative stress and thereby aggravates myocardial fibrosis and diastolic dysfunction in hypertensive female rats. The findings provide insight into the mechanism underlying diastolic dysfunction in hypertensive postmenopausal women. Hypertension Research (2011) 34, 496-502; doi:10.1038/hr.2010; published online 20 January 2011Keywords: estradiol; gender medicine; macrophage; myocardial fibrosis; oxidative stress INTRODUCTIONThe ejection fraction of the left ventricle (LV) is normal in approximately half of all patients with congestive heart failure, which indicates that impaired diastolic function in these patients is the major cause of heart failure. [1][2][3] Hypertension is the most common coexisting disease in patients with diastolic heart failure. Diastolic heart failure is more prevalent in women than in men, especially in postmenopausal hypertensive women, which may be due to decreased estrogen levels. 2,3 Determinants of diastolic function include active myocardial relaxation and passive properties of the LV wall. 2 Sequestration of calcium and cross-bridge uncoupling after systole are involved in the active process of relaxation. Previous studies have shown that estrogen

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“…23 The shortest transverse myocyte diameter and the percent area of myocardial fibrosis, respectively, were measured in three independent hematoxylin/eosin-stained sections and Mallory-Azan-stained sections of each rat. 23,24 Macrophages labeled with an antibody for ED-1 (Chemicon International, Temecula, CA, USA) were counted at Â200 magnification in three independent entire cross-sections of each animal. 25 …”

Section: Morphometric Analysis and Immunohistostainingmentioning

confidence: 99%

Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras–ERK pathways

et al. 2010

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Pronounced variability in blood pressure (BP) is an aggravating factor of hypertensive end-organ damage. However, its pathogenesis remains unknown. Statins have various protective effects on the cardiovascular system. Thus, we determined whether simvastatin would attenuate the aggravation of hypertensive cardiac remodeling in a rat model of hypertension with large BP variability, and also investigated the signaling mechanism involved in its effect. A model of hypertension with large BP variability was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). A SAD or sham operation was performed in 12-week-old rats. Thereafter, simvastatin (0.2 mg kg À1 per day) or vehicle was intraperitoneally administered every day. After 6 weeks , telemetric recordings revealed that SAD enhanced BP variability without changing the mean BP. SAD increased myocyte hypertrophy, myocardial fibrosis and macrophage infiltration associated with the upregulation of brain natriuretic peptide (BNP), type I procollagen, transforming growth factor (TGF)-b and monocyte chemoattractant protein (MCP)-1, and activation of RhoA, Ras and ERK1/2. Simvastatin did not change the mean BP or BP variability in SAD-operated SHRs. In SAD-operated SHRs, simvastatin attenuated myocyte hypertrophy and BNP expression, as well as RhoA, Ras and ERK1/2 activities. In contrast, simvastatin did not change myocardial fibrosis, macrophage infiltration, or the expression of procollagen and TGF-b or MCP-1 in SAD-operated SHRs. Simvastatin did not affect serum lipid levels. In conclusion, simvastatin attenuated the large BP variability-induced aggravation of cardiac hypertrophy, but not myocardial fibrosis, in SHRs. The activation of RhoA/Ras-ERK pathways may contribute to the aggravation of cardiac hypertrophy by a combination of hypertension and large BP variability.

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Expression of Proto-oncogenes and Gene Mutation of Sarcomeric Proteins in Patients With Hypertrophic Cardiomyopathy

Cited by 84 publications

References 43 publications

Molecular mechanism of size control in development and human diseases

Molecular mechanism of size control in development and human diseases

Enhanced cardiac inflammation and fibrosis in ovariectomized hypertensive rats: a possible mechanism of diastolic dysfunction in postmenopausal women

Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras–ERK pathways

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