JNK modulates FOXO3a for the expression of the mitochondrial death and mitophagy marker BNIP3 in pathological hypertrophy and in heart failure.

Bcl-2 E1B 19-KDa interacting protein 3 (BNIP3) is a mitochondrial death and mitophagy marker, which is involved in inducing cardiac remodeling post myocardial infarction. In this study, we show that BNIP3 expression increases in stressed cardiomyocytes in vitro and in response to pressure overload in vivo, and that its transcription is directly related to JNK activity. BNIP3 expression gradually increased in the first weeks after pressure overload and peaked at the heart failure stage. Ultrastructurally, the mitochondrial area was inversely proportional to BNIP3 expression. Both JNK and AKT activities increased with pressure overload; however, JNK signaling dominated over AKT signaling for the activation of the transcription factor FOXO3a and for the transcription of its effector, BNIP3. 3-methyladenine attenuated JNK signaling and significantly decreased BNIP3 expression and reversed cardiac remodeling in heart failure. Ultrastructurally, the mitochondrial area was significantly increased in the 3-methyladenine group compared with placebo. Moreover, adenoviral gene delivery of dominant negative JNK in a rat model of pressure overload hypertrophy abolished the increase in BNIP3 expression in response to pressure overload. These results suggest that JNK signaling is a critical modulator of the transcription factor FOXO3a driving the expression of its effector, BNIP3, in heart failure and that JNK, through BNIP3, induces mitochondrial apoptosis and mitophagy.

Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo.

Recombinant adeno-associated (AAV) viruses have unique properties, which make them ideal vectors for gene transfer targeting the myocardium. Numerous serotypes of AAV have been identified with variable tropisms towards cardiac tissue. In the present study, we investigated the time course of expression of eight different AAV serotypes in rat myocardium and the nature of the immunity against these serotypes. We first assessed whether neutralizing antibodies (NAb) were present for any of the serotype in the rats. We injected 100 microl of each AAV 1-8 serotype (10(12) DNAse resistant particles/ml), encoding LacZ gene, into the apical wall of rat myocardium. At 1, 4, 12 and 24 weeks after gene delivery, the animals were killed and beta-galactosidase (beta-gal) activity was assessed by luminometry. Additionally, LacZ genomic copies and AAV capsids copies were measured through standard polymerase chain reaction analysis and cryo-sections from the area of viral injection were stained for X-gal detection at the same time points. No NAbs were detected against any of AAV serotypes. At all the time points studied, AAV1, 6 and 8 demonstrated the highest efficiency in transducing rat hearts in vivo. Parallel to the results with beta-gal activity, the highest levels LacZ and AAV DNA genomic copies were with AAV1, 6 and 8. The positive X-gal staining depicted by these serotypes confirmed these results. These results indicate that among the various AAV serotypes, AAV1, 6 and 8 have differential tropism for the heart unaffected by pre-existing NAb in the rat. Although AAV 1 and 6 vectors induced rapid and robust expression and reach a plateau at 4 weeks, AAV 8 continued increasing until the end of the study. AAV 2, 5 and 7 vectors were slower to induce expression of the reporter gene, but did reach levels of expression comparable to AAV1 and AAV6 vectors after 3 months.

Tracking stem cells in vivo.

Stem cells have been targeted to many organ systems specifically to replace scarred organs and to rejuvenate diseased organs. Even though our understanding of the versatility of stem cells is slowly unraveling, tracking these cells as they enter the body has become a very important field of study. In this chapter, we review various modalities for imaging stem cells and assess the advantages and shortcomings of each technique.

[Comparison of central pulse pressure estimated from pulse wave propagation velocity and carotid pulse pressure measured by applantation tonometry]. / Comparaison de la pression pulsée centrale estimée à partir des vitesses de propagation de l'onde du pouls et de la pression pulsée carotidienne mesurée par tonométrie d'aplanation.

BACKGROUND: Pulse pressure (PP) corresponds to the difference between arterial systolic blood pressure and diastolic blood pressure. Central PP seems to be a stronger coronary risk marker than brachial PP. Central PP can be estimated by aortic PP measured non invasively by aplanation tonometry of the carotid artery. The aim of this study was to compare 2 methods of estimation of aortic PP: estimation from Pulse Wave Velocities (PWV) and by aplanation tonometry of the carotid artery. Estimation from PWV is based on the non uniform transmission of the PP i.e. the amplification of PP from the aorta to brachial artery, through arteries of increasing impedance. METHODS: One hundred and fifty one subjects were included, 111 hemodialysis patients and 40 subjects free of cardiovascular treatment or cardiovascular organ damage, recruited in a preventive medicine setting. Central PP was measured by aplanation tonometry of the carotid artery. The following formula was used for the relationship between PP and PWV in the two arterial segments considered for pulse wave travel (waterhammer formula): [formula: see text] Where measurement of brachial PP (PPBr) and PWV at aortic (PWVAo) and brachial (PWVBr) gives an estimation of aortic PP (PPAo estimated). Carotid-femoral PWV was used for PWVAo and carotid-radial PWV was used for PWVBr. The two methods were compared by t-test and according to Bland and Altman's method. RESULTS: In the hemodialysis group (73 males, 44 +/- 12 years old), brachial PP was 56 +/- 15 mm Hg and central PP as measured at the carotid level was 47 +/- 15 mmHg. In the healthy group (29 males, 46 +/- 11 years old), these values were 46 +/- 10 mmHg and 35 +/- 10 mmHg respectively. Compared to carotid artery aplanation tonometry, PPAo estimated was larger than central PP by 2.9 +/- 6.3 mmHg in hemodialysis patients and by 5.4 +/- 6.6 mmHg in the healthy group. The difference was significantly larger in healthy subjects than in hemodialysis patients (p = 0.031). CONCLUSION: The PWV estimated PP is larger than the central PP measured at the carotid level by aplanation tonometry. The difference is larger in cardiovascular event free subjects than in patients on hemodialysis.

[Progressive myoclonic epilepsy type Lafora]. / Epilepsie myoclonique progressive type Lafora.

Lafora's disease is a form of progressive myoclonic epilepsy characterized by seizures, myoclonus and dementia. We present the case of a 12-year-old girl who is complaining of epilepsy and myoclonic jerks starting a year ago, with deterioration of school performance, and abnormal EEG. The axillary skin biopsy showed PAS-positive inclusions in the cells of sweat glands, typical of Lafora's disease.