Early Development of Cardiac Fibrosis in Young Old-Father Offspring.

Cardiac aging is characterized by progressive fibrosis. Epidemiological studies have found that advanced paternal age is associated with an increased risk of heart failure in the next generation. This study is aimed at evaluating the effect of paternal age, in the young male rat progeny, on cardiac phenotype under circulatory stress conditions. Offspring rats were obtained by mating old males (24 months old) with young females (two months old) and by mating young males (two months old) with the same young females. Hypertension was induced in old father offspring (OFO) rats and young old father (YFO) offspring rats using L-NAME (N(ω)-nitro-L-arginine methyl ester). The OFO L-NAME rats showed a high blood pressure phenotype associated with substantial cardiac hypertrophy and an exacerbation of cardiac fibrosis compared to the YFO L-NAME rats. Histological analysis of heart tissue showed an expansion of the extracellular matrix, with fibroblasts displaying markers of epicardial origin (Tcf21, Tbx18, and Wt1) in the OFO group. Moreover, western blot and protein phosphorylation antibody array identified the TGF-ß2 receptor pathway as preferentially activated in aged hearts as well as in OFO cardiac tissue treated with L-NAME. In addition, old father offspring rats (OFO+OFO L-NAME) had increased cardiac DNA methylation. In young hypertensive progeny, advanced paternal age at conception may be a risk factor for early progression towards cardiac fibrosis. An intergenerational transmission may be behind the paternal age-related cardiac remodeling in the young offspring.

Beneficial role of simvastatin in experimental autoimmune myositis.

OBJECTIVE: Statins have immunomodulatory potential in autoimmune diseases but had not been studied as a disease-modifying agent in inflammatory myopathies. The objective of this study is to assess the effect of simvastatin in an experimental model of autoimmune myositis in mice on muscle strength and histopathology. METHODS: Four groups of mice (n = 5 per group) were selected for experimentally induced myositis. Mice were immunized with 1.5 mg myosin in complete Freund's adjuvant weekly for two times and injected with 500 ng pertussis toxin twice immediately after each immunization. From day 1 before immunization to 10 days after the last immunization, mice were treated with oral simvastatin (10 or 20 or 40 mg/kg) diluted in DMSO. The control group mice were injected with complete Freund's adjuvant weekly for two times and did not receive treatment. Non-immunized mice (n = 5 per group) were treated either with simvastatin (5 mg/kg or 20 mg/kg or 40 mg/kg of simvastatin diluted in DMSO) or with DMSO. RESULTS: Inflammation was observed in myositis groups with positive myositis-specific antibodies. Muscle strength dropped significantly after immunization. Immunized simvastatin 20 mg/kg treated group had significantly higher muscle strength versus non-treated myositis mice and versus other simvastatin doses. Besides, a trend toward higher serum Th17 percentage population was found in immunized non-treated mice, versus immunized simvastatin- treated mice, without significant difference. CONCLUSION: Simvastatin at 20 mg/kg decreases the severity of myositis in experimental autoimmune myositis and is a candidate of being a disease-modifying agent in inflammatory myopathies.

Intradialytic hypotension: beyond hemodynamics.

Intradialytic hypotension is a major complication during hemodialysis session, associated with increased risk of cardiovascular events and mortality. Its pathophysiology is believed to be multifactorial and remains not well elucidated. The aim of this study is to put forward new mechanisms behind the development of intradialytic hypotension. The study included sixty-five subjects on chronic hemodialysis, divided into two groups: intradialytic hypotensive (n=12) and normotensive (n=53), according to the variation of systolic blood pressure between post-dialysis and pre-dialysis measurements. Renin and angiotensin converting enzyme I plasma concentrations increased in both groups but more likely in normotensive group. Aldosterone plasma concentration is increased in the normotensive group while it decreased in the intradialytic hypotension group. Plasma endothelin concentrations showed higher values in intradialytic hypotension group. Post-dialysis asymmetric dimethylarginine and angiotensin converting enzyme 2 plasma concentrations were significantly higher in intradialytic hypotension group as compared to normotensive one. Collectrin plasma concentrations were significantly lower in intradialytic hypotension group. Finally, post-dialysis vascular endothelial growth factor C plasma concentration significantly increased in intradialytic hypotension group. In conclusion, endothelial dysfunction characterized by a lower level of vasoactive molecule seems to play a critical role in intradialytic hypotension development.

[The effect of methylphenidate on appetite and weight]. / L'effet de la méthylphénidate sur l'appétit et le poids.

OBJECTIVES: To better delineate in the medical literature the effect of methylphenidate on weight and appetite. METHODS: A search on PubMed was carried out for articles published with no restrictions on language or year of publication using the terms: "methylphenidate"; "weight"; "appetite". RESULTS: Methylphenidate increases dopamine and noradrenaline in synapses because of its blockage of the transporters of these monoamines in the frontal cortex and insular lobe. The intracerebral activity of methylphenidate is incriminated in the dysregulation of appetite due to its probable effect stimulating the disgust sensation generated after the activation of the insular lobe by the drug. The anorexigenic effect of methylphenidate has been demonstrated in preclinical studies although the dosage and the administration routes differ in animals from those used for human beings. In clinical studies, methylphenidate decreases the weight of children and adolescents during the first 3 to 6 months after its initiation due to the appetite reduction effect that it generates with a tendency of weight curves to rejoin the curves of subjects who did not receive the treatment a few years after its initiation. CONCLUSION: The anorexigenic effect of methylphenidate does not persist over the long-term in children and adolescents who receive it.

Effects of atrial natriuretic peptide on rat ventricular fibroblasts during differentiation into myofibroblasts.

Atrial natriuretic peptide antifibrotic properties are mainly described in cardiac myocytes or in induced cardiac myofibroblasts (Angiotensin II or TGF-beta induced differentiation). In the present work, we investigate the effects of ANP/NPRA/cGMP system in modulating rat cardiac fibroblasts function. Cardiac fibroblasts were isolated from adult Wistar male rats and cultured in the presence of serum in order to induce fibroblasts differentiation. Cultures were then treated with ANP (1 microM), 8-Br-cGMP (100 microM) or IBMX (100 microM), a non-specific phosphodiesterases inhibitor. ANP significantly decreased proliferation rate and collagen secretion. Its effect was mimicked by the cGMP analog, while combining ANP with 8-Br-cGMP did not lead to additional effects. Moreover intracellular cGMP levels were elevated when cells were incubated with ANP confirming that ANP intracellular pathway is mediated by cGMP. Additionally, immunoblotting and immunofluorescence were used to confirm the presence of guanylyl cyclase specific natriuretic peptide receptors A and B. Finally we scanned specific cGMP dependent PDEs via RT-qPCR, and noticed that inhibiting all PDEs led to an important decrease in proliferation rate. Effect of ANP became more prominent after 10 culture days, confirming the importance of ANP in fibroblasts to myofibroblasts differentiation. Uncovering cellular aspects of ANP/NPRA/cGMP signaling system provided more elements to help understand cardiac fibrotic process.

Cardiorenal syndrome in hypertensive rats: microalbuminuria, inflammation and ventricular hypertrophy.

The aim of our study was to evaluate a possible association between microalbuminuria (MA), several low-grade inflammation factors and left ventricular hypertrophy (LVH) by using a pharmacological approach. This may provide new insights into the pathophysiologic mechanisms of the cardiorenal syndrome (CRS) linking early renal impairment with elevated cardiovascular risk. Two kidney-one clip (2K-1C) renovascular hypertension was induced in 24 male Wistar rats (220-250 g). After the development of hypertension, rats were divided into four groups: 2K-1C (untreated), calcium channel blocker (amlodipine-treated), angiotensin receptor blocker (losartan-treated) and peripheral vasodilator (hydralazine-treated), which were treated for 10 weeks. Rats in the 2K-1C group had all developed hypertension, a significant increase in plasma levels of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), brain natriuretic peptide (BNP) and C-reactive protein (CRP). Moreover MA and creatininaemia underwent a significant increase. Under treatment decreases were observed in systolic blood pressure (SBP), TNF-alpha, CRP, IL-6, BNP concentrations and creatininaemia. These results were related to the absence of MA which was significantly associated with reductions in cardiac mass and hypertrophy markers (BNP and beta-MHC gene expression) as well as renal interstitial inflammation. In conclusion, our results suggest that the reduction of MA is correlated with the decrease of the inflammatory components and seems to play an important role in protecting against cardiac hypertrophy and renal injury.

Microalbuminuria versus brain natriuretic peptide in cardiac hypertrophy of hypertensive rats.

The objective of this study was to assess a possible link between microalbuminuria (MA), a major risk factor of the cardiorenal syndrome and the brain natriuretic peptide (BNP), a marker of cardiac hypertrophy. Two kidney-one clip (2K-1C) renovascular hypertension was induced in 24 male Wistar rats (weighing 220-250 g). Rats were randomized into four groups for 8 weeks: Sham, not treated; Bos, treated with bosentan; Cap, treated with captopril; Bos/Cap, treated with both drugs. Blood pressure, plasma BNP and transforming growth factor beta1 (TGF-ß1) concentrations, microalbuminuria and creatininemia as well as cardiac mass, BNP, alpha- and beta-myosin heavy chain (MHC) gene expression and kidney histology were determined. Following stenosis, Sham rats developed hypertension (p < 0.001), an increase in BNP (p < 0.05) and TGF-ß1 (p < 0.005) concentrations, creatinine levels (p < 0.001), and urinary albumin (p < 0.001). Under drug treatment, decreases in blood pressure (p < 0.001), creatinine levels (p < 0.05), plasma TGF-ß1 (p < 0.005) and BNP (p < 0.05) concentrations, were concomitant with the absence of MA which was significantly correlated with reductions in cardiac mass (p < 0.05) and hypertrophy markers (BNP and ß-MHC gene expression) (p < 0.005) as well as in renal fibrosis. These findings suggest a potential link between microalbuminuria evolution and BNP as well as a possible effect of microalbuminuria-lowering therapy on halting the progression, or even inducing the regression of cardiac hypertrophy.