Overexpression of Bax Protein and Enhanced Apoptosis in the Left Ventricle of Spontaneously Hypertensive Rats

Fortuño, María Antonia; Ravassa, Susana; Etayo, Juan C.; Dı́ez, Javier

doi:10.1161/01.hyp.32.2.280

Cited by 117 publications

(124 citation statements)

References 41 publications

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“…Medical treatment did not significantly differ between patients with and without elevated cTnT in the present study. Experimental studies have shown that the long-term administration of an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin II receptor blocker (ARB) prevents cardiomyocyte apoptosis in spontaneously hypertensive rats, 32,33) which suggests that either ACE-I or ARB can suppress ongoing myocardial damage. Further investigation is required to determine the mechanism of ongoing myocardial damage and its treatment in hypertensive patients.…”

Section: Therapeutic Implications Of Ongoing Myocardial Damage In Hy-mentioning

confidence: 99%

Elevated Cardiac Troponin T Predicts Adverse Outcomes in Hypertensive Patients

et al. 2011

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SummaryOngoing myocardial damage detected as elevated serum cardiac troponin T (cTnT) indicates increased risk for future cardiac events in patients with chronic heart failure. Whether elevated cTnT is associated with adverse outcomes in patients with hypertension (HT) without left ventricular (LV) systolic dysfunction is unknown.We measured cTnT levels in 176 patients with essential HT without LV systolic dysfunction (LV ejection fraction ≤ 55%), renal failure, and prior cardiovascular or cerebrovascular diseases and 39 normal controls. Levels of cTnT were elevated ( ≥ 0.02 ng/mL) in 15 (9%) of the 176 patients and in 0 (0%) of the 39 normal controls (P = 0.04). The rate of diabetes mellitus (DM), the cardiothoracic ratio, plasma B-type natriuretic peptide (BNP) value, and LV mass index were significantly higher in patients with than without elevated cTnT (DM, 8/15 versus 29/161, P = 0.004; cardiothoracic ratio, 54.5 ± 4.5 versus 51.6 ± 5.2%, P = 0.04; BNP, 103.3 ± 142.3 versus 36.9 ± 50.7 pg/mL, P = 0.04; LV mass index, 227 ± 87 versus 152 ± 57 g/m 2 , P = 0.0001). Kaplan-Meier analysis demonstrated that significantly fewer (P < 0.000001) patients with, than without elevated cTnT remained free of events (hospitalization due to cardiovascular or cerebrovascular disease, n = 34). Stepwise Cox multivariate analysis revealed that elevated cTnT (hazard ratio, 6.58; P = 0.000001) and smoking (hazard ratio, 2.24; P = 0.04) were independent predictors of events.The present findings indicate that cTnT is a novel and useful predictor of future cardiovascular or cerebrovascular events in hypertensive patients. (Int Heart J 2011; 52: 164-169)

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Section: Therapeutic Implications Of Ongoing Myocardial Damage In Hy-mentioning

confidence: 99%

Elevated Cardiac Troponin T Predicts Adverse Outcomes in Hypertensive Patients

et al. 2011

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“…Interestingly, losartan also blocked stretch-induced apoptosis in cultured adult cardiomyocytes (Leri et al, 1998) suggesting that the Gq-coupled AT1 receptor mediates activation of apoptotic pathways by mechanical stretch. Several studies have shown that ACE inhibitors or AT receptor antagonists also block the cardiomyocyte apoptosis observed in spontaneously hypertensive rats Goussev et al, 1998;FortunÄ o et al, 1998).…”

Section: Gaq Signaling In Apoptosis and Failurementioning

confidence: 99%

G-proteins in growth and apoptosis: lessons from the heart

2001

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The acute contractile function of the heart is controlled by the e ects of released nonepinephrine (NE) on cardiac adrenergic receptors. NE can also act in a more chronic fashion to induce cardiomyocyte growth, characterized by cell enlargement (hypertrophy), increased protein synthesis, alterations in gene expression and addition of sarcomeres. These responses enhance cardiomyocyte contractile function and thus allow the heart to compensate for increased stress. The hypertrophic e ects of NE are mediated through Gq-coupled a 1 -adrenergic receptors and are mimicked by the actions of other neurohormones (endothelin, prostaglandin F 2a angiotensin II) that also act on Gq-coupled receptors. Activation of phospholipase C by Gq is necessary for these responses, and protein kinase C and MAP kinases have also been implicated. Gq stimulated cardiac hypertrophy is also evident in transgenic mouse models. In contrast, stimulation of G s -coupled b-adrenergic receptors or G i -coupled receptors do not directly e ect cardiomyocyte hypertrophy. Apoptosis is also induced by G-protein-coupled receptor stimulation in cardiomyocytes. Sustained or excessive activation of either Gq-or Gs-signaling pathways results in apoptotic loss of cardiomyocytes both in vitro and in vivo. Apoptosis is associated with decreased ventricular function in the failing heart. Cardiomyocytes provide an ideal model system for understanding the basis for G-protein mediated hypertrophy and apoptosis, and the mechanisms responsible for the transition from compensatory to deleterious levels of signaling. This information may prove critical for designing interventions that prevent the pathophysiological consequences of heart failure. Oncogene (2001) 20, 1626 ± 1634.

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“…Cardiomyocytes were distinguished from nonmyocytes by microscopic appearance; that is, well-shaped, elongated, and striated cells. 16 …”

Section: Histological Analysismentioning

confidence: 99%

“…5 AT 2 R has been shown to mediate induction of apoptosis in the PC12 cell line, 6 vascular smooth muscle cells, 7 vascular endothelium, 8 fibroblasts, 9 granulose cells in the rat ovary, 10 neurons from the rat brain, 11 and human fetal adrenal cells. 12 Recently, it has been reported that cardiac remodeling in various heart diseases involves a loss of cardiomyocytes due to apoptosis [13][14][15] and that Ang II stimulation induces cardiomyocyte apoptosis in vivo 13,14,16 and in vitro. [17][18][19] Ligandbinding experiments 1 indicated that AT 2 R as well as AT 1 R is expressed in the heart and that AT 2 R subtype is upregulated in the diseased heart.…”

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confidence: 99%

Apoptosis Is Not Increased in Myocardium Overexpressing Type 2 Angiotensin II Receptor in Transgenic Mice

et al. 2001

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Abstract-To determine whether angiotensin type 2 (AT 2 ) receptor stimulation induces apoptosis in cardiomyocytes in vivo, we developed transgenic mice overexpressing the AT 2 receptor in a cardiac-specific manner, using the ␣-myosin heavy-chain promoter. Ten-to 12-week-old male homozygous transgenic mice (nϭ44) and wild-type mice (nϭ44) were used. Both transgenic and wild-type mice were given either saline (control), a subpressor dose of angiotensin II (100 ng · kg Ϫ1 · min Ϫ1), a pressor dose of angiotensin II (1000 ng · kg Ϫ1 · min Ϫ1) for 14 days, a pressor dose of angiotensin II for 28 days to investigate the effects of stimulation on both angiotensin type 1 (AT 1 ) and AT 2 receptors, the AT 1 antagonist L158809 alone, or a combination of angiotensin II (1000 ng · kg Ϫ1 · min Ϫ1) and L158809 for 14 days to investigate the effects of selective AT 2 receptor stimulation. Apoptosis was analyzed in paraffin-embedded ventricular sections by the terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling (TUNEL) technique. In both transgenic and wild-type mice, administration of a subpressor dose of angiotensin II, L158809, or a combination of angiotensin II and L158809 did not significantly affect the tail-cuff blood pressure or heart-to-body weight ratio, whereas administration of a pressor dose of angiotensin II for 14 or 28 days significantly increased blood pressure and the heart-to-body weight ratio. However, there was no statistical difference between the effects of angiotensin II in transgenic and wild-type mice. The number of TUNEL-positive nuclei was Ϸ0 to 10 per 100 000 cardiomyocytes, with no difference between transgenic and wild-type mice, regardless of saline infusion or any stimulation. In infarcted canine myocardial tissue sections for positive control, the number of TUNEL-positive nuclei was increased by 13.8 to 19.1 times compared with those in the noninfarcted myocardium. In conclusion, angiotensin II infusion for a period of 28 days failed to induce cardiomyocyte apoptosis regardless of the presence or absence of cardiac AT 2 receptor overexpression. It is unlikely that in mice the AT 2 receptor is a strong signal to induce cardiomyocyte apoptosis in vivo. A ngiotensin (Ang) II has 2 major receptor isoforms: Ang II type 1 receptor (AT 1 R) and Ang II type 2 receptor (AT 2 R). Most of the well-known Ang II functions, such as increasing blood pressure, stimulating myocyte hypertrophy, and the proliferating effect in the cardiovascular system, are mediated by AT 1 R. 1-3 On the other hand, AT 2 R has been implicated in the inhibition of cell growth 4 and proliferation. 5 AT 2 R has been shown to mediate induction of apoptosis in the PC12 cell line, 6 vascular smooth muscle cells, 7 vascular endothelium, 8 fibroblasts, 9 granulose cells in the rat ovary, 10 neurons from the rat brain, 11 and human fetal adrenal cells. 12 Recently, it has been reported that cardiac remodeling in various heart diseases involves a loss of cardiomyocytes due to apoptosis [13][14][15] and that Ang II stimul...

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Overexpression of Bax Protein and Enhanced Apoptosis in the Left Ventricle of Spontaneously Hypertensive Rats

Cited by 117 publications

References 41 publications

Elevated Cardiac Troponin T Predicts Adverse Outcomes in Hypertensive Patients

Elevated Cardiac Troponin T Predicts Adverse Outcomes in Hypertensive Patients

G-proteins in growth and apoptosis: lessons from the heart

Apoptosis Is Not Increased in Myocardium Overexpressing Type 2 Angiotensin II Receptor in Transgenic Mice

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