RESUMEN
Nitric oxide (NO) donors may be useful for treating pulmonary hypertension (PH) complicating sickle cell disease (SCD), as endogenous NO is inactivated by hemoglobin released by intravascular hemolysis. Here, we investigated the effects of the new NO donor NCX1443 on PH in transgenic SAD mice, which exhibit mild SCD without severe hemolytic anemia. In SAD and wild-type (WT) mice, the pulmonary pressure response to acute hypoxia was similar and was abolished by 100 mg/kg NCX1443. The level of PH was also similar in SAD and WT mice exposed to chronic hypoxia (9% O2) alone or with SU5416 and was similarly reduced by daily NCX1443 gavage. Compared with WT mice, SAD mice exhibited higher levels of HO-1, endothelial NO synthase, and PDE5 but similar levels of lung cyclic guanosine monophosphate. Cultured pulmonary artery smooth muscle cells from SAD mice grew faster than those from WT mice and had higher PDE5 protein levels. Combining NCX1443 and a PDE5 inhibitor suppressed the growth rate difference between SAD and WT cells and induced a larger reduction in hypoxic PH severity in SAD than in WT mice. By amplifying endogenous protective mechanisms, NCX1443 in combination with PDE5 inhibition may prove useful for treating PH complicating SCD.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antihipertensivos/farmacología , Presión Arterial/efectos de los fármacos , Hipertensión Pulmonar/prevención & control , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico/metabolismo , Arteria Pulmonar/efectos de los fármacos , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/metabolismo , Animales , Antihipertensivos/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , GMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Modelos Animales de Enfermedad , Hemo-Oxigenasa 1/metabolismo , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipoxia/complicaciones , Masculino , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Donantes de Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Inhibidores de Fosfodiesterasa 5/farmacología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatologíaRESUMEN
Telomere shortening is associated with COPD and impaired lung function in cross-sectional studies, but there is no longitudinal study. We used data from 448 participants recruited as part of the French follow-up of the European Community Respiratory Health Survey. We found no relationship between telomere length at baseline and FEV1 decline after 11 years of follow-up. However, heavy smoking was associated with an accelerated FEV1 decline in individuals with short telomeres, but not in subjects with longer telomeres (p for interaction p=0.08). Our findings suggest that short telomere length in peripheral leucocytes might be a marker for increased susceptibility to the effect of smoking.
Asunto(s)
Volumen Espiratorio Forzado/fisiología , Pulmón/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/genética , Fumar/efectos adversos , Telómero/metabolismo , Adulto , Biomarcadores/metabolismo , Estudios Transversales , Femenino , Estudios de Seguimiento , Volumen Espiratorio Forzado/genética , Francia , Encuestas Epidemiológicas , Humanos , Leucocitos , Estudios Longitudinales , Masculino , Factores de Riesgo , Espirometría/métodos , Homeostasis del Telómero , Acortamiento del Telómero , Adulto JovenRESUMEN
RATIONALE: Sleep disorders may lead to stress-induced premature aging and telomere shortening. OBJECTIVES: To determine whether obstructive sleep apnea syndrome causing intermittent hypoxemic episodes was associated with telomere shortening independently from the comorbidities associated with this syndrome. METHODS: We conducted a cross-sectional study in 161prospectivelly enrolled, untreated, middle-aged men free of known comorbidities related or unrelated to sleep apnea. Each participant underwent full standard overnight polysomnography. Patients with apnea sleep syndrome were naive to treatment. MEASUREMENTS AND MAIN RESULTS: In univariate analysis, we found that telomere shortening was associated with older age, apnea-hypopnea index, oxygen desaturation index, waist circumference, and fat mass. After adjustment for age, only apnea-hypopnea index and oxygen desaturation index were significantly related to telomere shortening. The mean telomere length ratio was 0.70 ± 0.37 in the participants without sleep apnea, compared with 0.61 ± 0.22 and 0.53 ± 0.16 in those with mild to moderate and severe sleep apnea, respectively (P = 0.01). In multivariate analysis, we found that oxygen desaturation index was the only factor independently associated with telomere length. Arterial stiffness assessed by carotid-femoral pulse wave velocity correlated negatively with telomere length. CONCLUSIONS: Intermittent hypoxemia due to obstructive sleep apnea syndrome is a major contributor to telomere shortening in middle-aged men. Oxidative stress may explain this finding.
Asunto(s)
Envejecimiento/genética , Síndromes de la Apnea del Sueño/genética , Síndromes de la Apnea del Sueño/fisiopatología , Acortamiento del Telómero , Adulto , Comorbilidad , Estudios Transversales , Francia , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Modelos Genéticos , Análisis Multivariante , Polisomnografía , Estudios Prospectivos , Análisis de la Onda del Pulso , Índice de Severidad de la EnfermedadRESUMEN
We assessed the involvement of harmonin-b, a submembranous protein containing PDZ domains, in the mechanoelectrical transduction machinery of inner ear hair cells. Harmonin-b is located in the region of the upper insertion point of the tip link that joins adjacent stereocilia from different rows and that is believed to gate transducer channel(s) located in the region of the tip link's lower insertion point. In Ush1c (dfcr-2J/dfcr-2J) mutant mice defective for harmonin-b, step deflections of the hair bundle evoked transduction currents with altered speed and extent of adaptation. In utricular hair cells, hair bundle morphology and maximal transduction currents were similar to those observed in wild-type mice, but adaptation was faster and more complete. Cochlear outer hair cells displayed reduced maximal transduction currents, which may be the consequence of moderate structural anomalies of their hair bundles. Their adaptation was slower and displayed a variable extent. The latter was positively correlated with the magnitude of the maximal transduction current, but the cells that showed the largest currents could be either hyperadaptive or hypoadaptive. To interpret our observations, we used a theoretical description of mechanoelectrical transduction based on the gating spring theory and a motor model of adaptation. Simulations could account for the characteristics of transduction currents in wild-type and mutant hair cells, both vestibular and cochlear. They led us to conclude that harmonin-b operates as an intracellular link that limits adaptation and engages adaptation motors, a dual role consistent with the scaffolding property of the protein and its binding to both actin filaments and the tip link component cadherin-23.
Asunto(s)
Adaptación Fisiológica , Proteínas Portadoras/metabolismo , Células Ciliadas Auditivas Internas/metabolismo , Mecanotransducción Celular/fisiología , Potenciales de Acción/fisiología , Animales , Proteínas de Ciclo Celular , Proteínas del Citoesqueleto , Técnica del Anticuerpo Fluorescente , Ratones , Ratones Mutantes , Microscopía Electrónica de Rastreo , Técnicas de Placa-ClampRESUMEN
The planar polarity and staircase-like pattern of the hair bundle are essential to the mechanoelectrical transduction function of inner ear sensory cells. Mutations in genes encoding myosin VIIa, harmonin, cadherin 23, protocadherin 15 or sans cause Usher syndrome type I (USH1, characterized by congenital deafness, vestibular dysfunction and retinitis pigmentosa leading to blindness) in humans and hair bundle disorganization in mice. Whether the USH1 proteins are involved in common hair bundle morphogenetic processes is unknown. Here, we show that mouse models for the five USH1 genetic forms share hair bundle morphological defects. Hair bundle fragmentation and misorientation (25-52 degrees mean kinociliary deviation, depending on the mutant) were detected as early as embryonic day 17. Abnormal differential elongation of stereocilia rows occurred in the first postnatal days. In the emerging hair bundles, myosin VIIa, the actin-binding submembrane protein harmonin-b, and the interstereocilia-kinocilium lateral link components cadherin 23 and protocadherin 15, all concentrated at stereocilia tips, in accordance with their known in vitro interactions. Soon after birth, harmonin-b switched from the tip of the stereocilia to the upper end of the tip link, which also comprises cadherin 23 and protocadherin 15. This positional change did not occur in mice deficient for cadherin 23 or protocadherin 15. We suggest that tension forces applied to the early lateral links and to the tip link, both of which can be anchored to actin filaments via harmonin-b, play a key role in hair bundle cohesion and proper orientation for the former, and in stereociliary elongation for the latter.