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Chronic hypoxia has been shown to stimulate myocardial microvascular growth and improve cardiac ischemic tolerance in young and adult rats. The aim of this study was to determine whether the ANG II type 1 receptor (A[T.sub.1]) pathway was involved in these processes. Newborn Wistar rats, exposed to chronic intermittent hypoxia (8 h/day) for 10 days, were simultaneously treated with A[T.sub.1] receptor blocker irbesartan and compared with untreated animals. The major finding is that chronic hypoxia increased the capillary supply of myocardial tissue, which was even more pronounced in hypertrophied right ventricle, whereas increased arteriolar supply was found only in the left ventricle. This angiogenic response was completely prevented by irbesartan. Moreover, chronic hypoxia improved the postischemic recovery of cardiac contractile function during reperfusion, and this protective effect was also completely abolished by irbesartan. Chronic hypoxia increased the myocardial density of A[T.sub.1] but not of ANG II type 2 receptor subtypes, whereas the effect of irbesartan was not significant. The expression of caveolin-1[alpha] markedly increased in response to chronic hypoxia, and irbesartan prevented this effect. Neither hypoxia nor irbesartan treatment altered the expression of nitric oxide synthase 3, heat shock protein 90, and VEGF. It is concluded that the A[T.sub.1] receptor pathway plays an important role in coronary angiogenesis and improved cardiac ischemic tolerance induced in neonatal rats by chronic hypoxia. angiotensin II receptors; ischemia-reperfusion; caveolin-1

Right ventricular myocardial hypertrophy during hypoxic pulmonary hypertension is associated with local renin-angiotensin system activation. The expression of angiotensin II type 1 (A[T.sub.1]) and type 2 (A[T.sub.2]) receptors in this setting has never been investigated. We have therefore examined the chronic hypoxia pattern of A[T.sub.1] and A[T.sub.2] expression in the right and left cardiac ventricles, using in situ binding and RT-PCR assays. Hypoxia produced right, but not left, ventricular hypertrophy after 7, 14, and 21 days, respectively. Hypoxia for 2 days was associated in each ventricle with a simultaneous and transient increase (P < 0.05) in A[T.sub.1] binding and A[T.sub.1] mRNA levels in the absence of any significant change in A[T.sub.2] expression level. Only after 14 days of hypoxia, A[T.sub.2] binding increased (P < 0.05) in the two ventricles, concomitantly with a right ventricular decrease (P < 0.05) in A[T.sub.2] mRNA. Along these data, A[T.sub.1] and A[T.sub.2] binding remained unchanged in both the left and hypertrophied right ventricles from rats treated with monocrotaline for 30 days. These results indicate that chronic hypoxia induces modulations of A[T.sub.1] and A[T.sub.2] receptors in both cardiac ventricles probably through direct and indirect mechanisms, respectively, which modulations may participate in myogenic (at the level of smooth or striated myocytes) rather than in the growth response of the heart to hypoxia. chronic hypoxia; heart ventricles; angiotensin II; A[T.sub.1] and A[T.sub.2] receptor subtypes

To explore the vascular function of the angiotensin II (ANG II) A[T.sub.2] receptor subtype (A[T.sub.2]R), we generated a vascular smooth muscle cell (SMC) line expressing the A[T.sub.2]R (SMC-vA[T.sub.2]). The involvement of A[T.sub.2]R in the motility response of SMCs was examined in SMC-vA[T.SUB.2] cells and their controls (SMC-v) cultured on either laminin or fibronectin matrix proteins with the agarose drop technique. All experiments were conducted in the presence of a saturating concentration of losartan to inactivate the A[T.sub.1]R subtype. Under basal conditions, both cell lines migrated outside drops, but on laminin only. Treatment with ANG II significantly inhibited the migration of SMC-vA[T.sub.2] but not SMC-v cells, and this effect was prevented by the A[T.sub.2]R antagonist CGP-42112A. The decreased migration of SMC-vA[T.sub.2] was not associated with changes in cell growth, cytoskeleton stiffness, or smooth muscle actin, desmin, and tenascin expression. However, it was correlated with increased synthesis and binding of fibronectin. Both responses were prevented by incubation with selective A[T.sub.2]R antagonists. Addition of GRGDTP peptide, which prevents cell attachment of fibronectin, reversed the A[T.sub.2]R inhibitory effect on SMC-vA[T.sub.2] migration. These results suggest that activated ANG II A[T.sub.2]R inhibits SMC migration via cellular fibronectin synthesis and associated cell binding. vascular smooth muscle cells; laminin and fibronectin substrates; cellular fibronectin

Objectives: Fibrosis is a classical feature of cardiac hypertrophy. To date changes within the basal lamina during normal and pathological cardiac growth have been poorly investigated. The goal of the present study was to determine if the expression of the muscle specific subunit of merosin (laminin α2 chain) together with that of fibronectin (FN) is modified in the diseased human heart. Laminin α2 chain expression was also investigated during physiological and pathological cardiac growth in the rat. Methods: In ten normal human hearts and ten hearts with idiopathic dilated cardiomyopathy (IDCM), the laminin-α2 and FN mRNA levels were quantified by slot-blot using total RNA and the protein distribution was analysed using an immunofluorescence approach. In Wistar rats, laminin α2 and FN mRNA expression was analyzed using RNase protection assay (RPA) and slot-blot assays. Results: The amount of laminin α2 mRNA did not vary in normal and pathological human hearts whereas it was significantly decreased in renovascular hypertensive rats (−20%) P<0.05 versus normal tissue). The amount of fibronectin mRNA increased in IDMC patients (×2, P<0.05 versus normal tissue), but was unchanged in hypertensive rats. A negative correlation was found between the cardiac laminin-α2 level and the age of the patients whatever the cardiac status. During postnatal development in the rat, a similar decrease in cardiac laminin-α2 level was observed between 3 and 30 weeks of age. Finally, the immunofluorescent approach failed to detect any alteration in laminin α2 distribution within the human myocardium. Conclusion: These data indicate that an imbalance between myocyte hypertrophy and the level of laminin-α2 might contribute to alterations in sarcolemmal properties, which occur during the development of cardiac hypertrophy and its transition to cardiac failure. [ABSTRACT FROM PUBLISHER]

High-dose chemotherapy and autologous marrow or peripheral stem cell support offers the best chance of cure in some subgroups of patients with non-Hodgkin's lymphoma (NHL). Less is known about the role of a second course of myeloablative chemotherapy in patients who relapse after a first autologous transplant. The aim of this retrospective study was to evaluate the disease outcome, morbidity and mortality associated with second autologous transplantation in patients with NHL. Between 1985 and 2001, 225 patients who had received autologous transplantation for NHL in two institutions in Lyon relapsed. Of these 225 patients 18 underwent a second autologous transplantation. The median age at second transplant was 41 years. There were six indolent lymphomas and 12 aggressive lymphomas. The median follow-up from the second transplant was 42 months. The OS rate at 2 and 5 years were 58 and 27%, respectively. The PFS rate at 2 and 5 years was 36%. Five patients are alive without disease 20 to 100 months after the second transplant. Seven patients died of disease recurrence. Four (22%) toxic deaths occurred: one of pulmonary fibrosis, one of fungal infection and cardiac failure and two of acute leukaemia. A minority of patients with NHL recurrence after a first transplant can be cured by a second course of myeloablative chemotherapy at the cost however of high-risk toxic death. [ABSTRACT FROM AUTHOR]