Stage-dependent activation of cell cycle and apoptosis mechanisms in the right ventricle by pressure overload

Ecarnot-Laubriet, Aline; Assem, Mahfoud; Poirson-Bichat, F.; Moisant, Maryvonne; Bernard, C.; Lecour, Sandrine; Solary, Éric; Rochette, Luc; Teyssier, Jean-Raymond

doi:10.1016/s0925-4439(01)00101-6

Cited by 28 publications

(23 citation statements)

References 23 publications

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“…We found that apoptosis started early and declined when clinically manifest RV failure occurred. This finding is consistent with other pressure-overload mediated RV disease studies (11,12).…”

Section: Discussionsupporting

confidence: 93%

“…Apoptosis and fibrosis have been shown to act in isolation or in concert to reduce LV performance (9,10). In contrast, the association of apoptosis with RV disease progression (11,12) is unclear. Recently, in vivo imaging of cardiac apoptosis with 99m Tc-annexin V ( 99m Tc-annexin) was proven feasible, because 99m Tc-annexin binds to exposed phosphatidylserine on the outer surface of apoptotic cells (13).…”

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confidence: 99%

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Serial Noninvasive Assessment of Apoptosis During Right Ventricular Disease Progression in Rats

Campian

Verberne²,

Hardziyenka³

et al. 2009

J Nucl Med

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Right ventricular (RV) function is the major determinant of survival in patients with pulmonary hypertension. Yet, the pathophysiologic basis of RV disease is unresolved. We aimed to study the role of apoptosis in RV disease by monitoring it serially during disease progression using in vivo 99m Tc-annexin-V ( 99m Tc-annexin) scintigraphy and study whether the reduction in apoptosis resulting from chronic treatment with valsartan can be detected by 99m Tc-annexin scintigraphy. Methods: RV disease after pulmonary hypertension was induced by monocrotaline injection in rats. The following 3 groups were studied: rats treated with monocrotaline (monocrotaline rats), rats treated with monocrotaline plus valsartan (valsartan rats), and age-matched controls (control rats). Serial echocardiography and in vivo 99m Tc-annexin scintigraphy were performed. Apoptosis was confirmed by 99m Tc-annexin autoradiography and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling. Fibrosis was assessed by picrosirius red staining. Results: In monocrotaline rats, in vivo 99m Tc-annexin uptake peaked early and declined thereafter but remained elevated, compared with baseline. These stage-dependent changes of in vivo 99m Tc-annexin uptake were paralleled by changes in autoradiography and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling. Valsartan rats had longer RV failurefree survival than did monocrotaline rats and had reduced apoptosis. These changes were accompanied by commensurate delays in RV hypertrophy and RV dilation. Valsartan rats also had less fibrosis than monocrotaline rats at all disease stages. Conclusion: RV disease progression is associated with an early increase in RV apoptosis, as monitored using serial in vivo 99m Tc-annexin scintigraphy. Delay in RV disease progression by valsartan is accompanied by reduction in RV apoptosis. Apoptosis plays a role in RV disease progression and may be assessed by serial in vivo 99m Tc-annexin scintigraphy.

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Serial Noninvasive Assessment of Apoptosis During Right Ventricular Disease Progression in Rats

Campian

Verberne²,

Hardziyenka³

et al. 2009

J Nucl Med

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“…There are evidences suggesting that cell cycle and apoptosis pathways are co-activated in pressure-overload RV in MCT model [5]. In this sequence, we assessed the LV myocardial apoptosis, and found increased rates of apoptosis both in MCT-4 and MCT-6.…”

Section: Edlvp) B End Diastolic LV Dimensions (Edlvd)mentioning

confidence: 89%

Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension

et al. 2009

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Although pulmonary hypertension (PH) selectively overloads the right ventricle (RV), neuroendocrine activation and intrinsic myocardial dysfunction have been described in the left ventricle (LV). In order to establish the timing of LV dysfunction development in PH and to clarify underlying molecular changes, Wistar rats were studied 4 and 6 weeks after subcutaneous injection of monocrotaline (MCT) 60 mg/kg (MCT-4, n = 11; MCT-6, n = 11) or vehicle (Ctrl-4, n = 11; Ctrl-6, n = 11). Acute single beat stepwise increases of systolic pressure were performed from baseline to isovolumetric (LVPiso). This hemodynamic stress was used to detect early changes in LV performance. Neurohumoral activation was evaluated by measuring angiotensin-converting enzyme (ACE) and endothelin-1 (ET-1) LV mRNA levels. Cardiomyocyte apoptosis was evaluated by TUNEL assay. Extracellular matrix composition was evaluated by tenascin-C mRNA levels and interstitial collagen content. Myosin heavy chain (MHC) composition of the LV was studied by protein quantification. MCT treatment increased RV pressures and RV/LV weight ratio, without changing LV end-diastolic pressures or dimensions. Baseline LV dysfunction were present only in MCT-6 rats. Afterload elevations prolonged s and upward-shifted end-diastolic pressure dimension relations in MCT-4 and even more in MCT-6. MHC-isoform switch, ACE upregulation and cardiomyocyte apoptosis were present in both MCT groups. Rats with severe PH develop LV dysfunction associated with ET-1 and tenascin-C overexpression. Diastolic dysfunction, however, could be elicited at earlier stages in response to hemodynamic stress, when only LV molecular changes, such as MHC isoform switch, ACE upregulation, and myocardial apoptosis were present.

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“…It is also worth noting that high levels of the antiapoptotic protein Bcl2 have been found in early stages of hypertrophy (67) and that arterial wall thickness, perivascular fibrosis, and cardiac hypertrophy induced by angiotensin II treatment are significantly reduced in Ets-1-deficient mice (68).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C (PKC)ζ-mediated Gαq Stimulation of ERK5 Protein Pathway in Cardiomyocytes and Cardiac Fibroblasts

García-Hoz

Sánchez-Fernández

García‐Escudero

et al. 2012

Journal of Biological Chemistry

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Background: We have recently described that G␣ q acts as an adaptor protein that facilitates PKC-mediated activation of ERK5. Results: Our results show that PKC is essential for Gq-dependent ERK5 activation in cardiomyocytes and cardiac fibroblasts. Conclusion: This novel signaling axis plays a key role in cardiac hypertrophy programs. Significance: The G␣ q /PKC/ERK5 pathway would be active in such pathological settings, providing new therapeutic targets.

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Stage-dependent activation of cell cycle and apoptosis mechanisms in the right ventricle by pressure overload

Cited by 28 publications

References 23 publications

Serial Noninvasive Assessment of Apoptosis During Right Ventricular Disease Progression in Rats

Serial Noninvasive Assessment of Apoptosis During Right Ventricular Disease Progression in Rats

Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension

Protein Kinase C (PKC)ζ-mediated Gαq Stimulation of ERK5 Protein Pathway in Cardiomyocytes and Cardiac Fibroblasts

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