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- Fong, L. G., et al.
(författare)
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Prelamin A and lamin A appear to be dispensable in the nuclear lamina
- 2006
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Ingår i: J Clin Invest. ; 116:3, s. 743-752
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Tidskriftsartikel (refereegranskat)abstract
- Lamin A and lamin C, both products of Lmna, are key components of the nuclear lamina. In the mouse, a deficiency in both lamin A and lamin C leads to slow growth, muscle weakness, and death by 6 weeks of age. Fibroblasts deficient in lamins A and C contain misshapen and structurally weakened nuclei, and emerin is mislocalized away from the nuclear envelope. The physiologic rationale for the existence of the 2 different Lmna products lamin A and lamin C is unclear, although several reports have suggested that lamin A may have particularly important functions, for example in the targeting of emerin and lamin C to the nuclear envelope. Here we report the development of lamin C-only mice (Lmna(LCO/LCO)), which produce lamin C but no lamin A or prelamin A (the precursor to lamin A). Lmna(LCO/LCO) mice were entirely healthy, and Lmna(LCO/LCO) cells displayed normal emerin targeting and exhibited only very minimal alterations in nuclear shape and nuclear deformability. Thus, at least in the mouse, prelamin A and lamin A appear to be dispensable. Nevertheless, an accumulation of farnesyl-prelamin A (as occurs with a deficiency in the prelamin A processing enzyme Zmpste24) caused dramatically misshapen nuclei and progeria-like disease phenotypes. The apparent dispensability of prelamin A suggested that lamin A-related progeroid syndromes might be treated with impunity by reducing prelamin A synthesis. Remarkably, the presence of a single Lmna(LCO) allele eliminated the nuclear shape abnormalities and progeria-like disease phenotypes in Zmpste24-/- mice. Moreover, treating Zmpste24-/- cells with a prelamin A-specific antisense oligonucleotide reduced prelamin A levels and significantly reduced the frequency of misshapen nuclei. These studies suggest a new therapeutic strategy for treating progeria and other lamin A diseases.
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| 4. |
- Phillips, Craig L, et al.
(författare)
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Effects of continuous positive airway pressure treatment and withdrawal in patients with obstructive sleep apnea on arterial stiffness and central BP.
- 2008
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Ingår i: Chest. - : Elsevier BV. - 0012-3692. ; 134:1, s. 94-100
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased BP and other cardiometabolic risk factors. The aim of the present study was to determine whether arterial stiffness and central BP (two important cardiovascular risk factors) would change, independent of peripheral BP following either the initiation of or withdrawal from nasal continuous positive airway pressure (CPAP) treatment in subjects with OSA. METHODS AND RESULTS: Arterial stiffness and peripheral and central BP were measured at baseline, and then either at 2 months after starting CPAP therapy (intervention group, n=20) or 7 nights after withdrawal from CPAP therapy (withdrawal group, n=20) using pulse wave analysis. In the intervention group, there were reductions in arterial stiffness (ie, the aortic augmentation index fell by 2.5%) and central systolic BP (fell by 4.2 mm Hg) without a concomitant reduction in peripheral BP. The change in arterial stiffness was associated with CPAP compliance (r=-0.47). In contrast, in the withdrawal group there were no overall changes in arterial stiffness or BP. However, there was an early morning increase in diastolic BP and heart rate relative to late evening. CONCLUSION: These results suggest that clinically important changes in arterial stiffness and central BP may occur following effective CPAP treatment of OSA without parallel changes in peripheral BP.
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