PCNA Up-Regulation in Cerebral Vessels with Angiotensin II-Hypertension: Abnormal Regulation of Ca2+Channel and Nitrate Tolerance Associated with Alternative Splicing of cGKI
| Autor: | L. V. Melnitchenko, Volodymyr Gerzanich, J. M. Simard, Alexander Ivanov, M. F. Shuba, Svetlana Ivanova |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
medicine.medical_specialty
Vascular smooth muscle biology Physiology Chemistry General Neuroscience Alternative splicing Dihydropyridine Angiotensin II Proliferating cell nuclear antigen Endocrinology Downregulation and upregulation Internal medicine medicine biology.protein Channel blocker Soluble guanylyl cyclase medicine.drug |
| Zdroj: | Neurophysiology. 35:181-186 |
| ISSN: | 0090-2977 |
| DOI: | 10.1023/b:neph.0000008778.34093.82 |
| Popis: | We studied the responses of the basilar arteries from control rats and from rats infused with angiotensin II (Ang; 240 μg/kg/h × 4 weeks), which were hypertensive (137 ± 13 vs 205 ± 10 mm Hg). Ang-hypertensive rats (AHR) showed significant up-regulation of the expression of proliferative cell nuclear antigen (PCNA) (PCNA index, 0.65) in vascular smooth muscle cell (VSMC) layers. Both hypertension and PCNA up-regulation were absent in animals co-treated with the hydrophilic dihydropyridine Ca2+ channel blocker amlodipine (100 mg/liter in the drinking water). Quantitative patch-clamp analysis of freshly isolated VSMC showed a significant increase in L-type Ca2+ channel currents in AHR that was attributed to an increase in the open channel probability, with no change in other biophysical properties, pharmacological characteristics, or in the channel expression. Compared with controls, regulation of Ca2+ channels in AHR was abnormal, with nitrate tolerance manifested as a reduction in down-regulation of the Ca2+ channel activity in response to the NO donor Na nitroprusside. A diminished sensitivity to 8-Br-cGMP was also observed, consistent with a mechanism downstream of soluble guanylyl cyclase. The nitrate tolerance was found to be attributable to alternative splicing of cGKI, with a decrease in the cGKIalpha expression and an increase in the cGKIbeta expression, with the latter known to be less sensitive to activation by cGMP and related analogs. We conclude that the increase in the proliferative response of VSMC in AHR is associated with an abnormal response to NO by VSMC due to alternative splicing of cGKI, resulting in an increase in the Ca2+ channel activation and up-regulation of the pro-proliferative Ca2+-sensitive gene for PCNA. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink