K+ Channels Expression in Hypertension After Arterial Injury, and Effect of Selective Kv1.3 Blockade with PAP-1 on Intimal Hyperplasia Formation

• Published in: Cardiovascular drugs and therapy Vol. 28; no. 6; pp. 501 - 511
• Main Authors: Cidad, P., Novensà, L., Garabito, M., Batlle, M., Dantas, A. P., Heras, M., López-López, J. R., Pérez-García, M. T., Roqué, M.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-12-2014; Springer
• Subjects: Animals; Arterial hypertension. Arterial hypotension; Arteries - drug effects; Arteries - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Cardiology; Cardiology. Vascular system; Cardiovascular system; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Essential Hypertension; Female; Hyperplasia - drug therapy; Hyperplasia - metabolism; Hypertension - drug therapy; Hypertension - metabolism; Kv1.3 Potassium Channel - antagonists & inhibitors; Kv1.3 Potassium Channel - metabolism; Male; Medical sciences; Medicine; Medicine & Public Health; Mice; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Original Article; Pancreatitis-Associated Proteins; Pharmacology. Drug treatments; Potassium Channel Blockers - pharmacology; Tunica Intima - drug effects; Tunica Intima - metabolism; Hypertension; K; channels; PAP-1; Intimal hyperplasia; Hyperplasia; Intima; Cardiovascular disease; Ionic channel
• ISSN: 0920-3206; 1573-7241
• DOI: 10.1007/s10557-014-6554-5

Introduction
K
+
channels are central to vascular pathophysiology. Previous results demonstrated that phenotypic modulation associates with a change in Kv1.3 to Kv1.5 expression, and that Kv1.3 blockade inhibits proliferation of VSMCs cultures.
Purpose
To explore whether the Kv1.3 to Kv1.5 switch could be a marker of the increased risk of intimal hyperplasia in essential hypertension and whether systemic treatment with Kv1.3 blockers can prevent intimal hyperplasia after endoluminal lesion .
Methods
Morphometric and immunohistochemical analysis were performed in arterial segments following arterial injury and constant infusion of the Kv1.3 blocker PAP-1 during 28 days. Differential expression of K
+
channel genes was studied in VSMC from hypertensive (BPH) and normotensive (BPN) mice, both in control and after endoluminal lesion. Finally, the migration and proliferation rate of BPN and BPH VSMCs was explored in vitro.
Results
Changes in mRNA expression led to an increased Kv1.3/Kv1.5 ratio in BPH VSMC. Consistent with this, arterial injury in BPH mice induced a higher degree of luminal stenosis, (84 ± 4 % vs. 70 ± 5 % in BPN,
p
 < 0.01), although no differences in migration and proliferation rate were observed in cultured VSMCs. The in vivo proliferative lesions were significantly decreased upon PAP-1 systemic infusion (18 ± 6 % vs. 58 ± 20 % with vehicle,
p
 < 0.05).
Conclusions
Hypertension leads to a higher degree of luminal stenosis in our arterial injury model, that correlates with a decreased expression of Kv1.5 channels. Kv1.3 blockers decreased in vitro VSMCs proliferation, migration, and in vivo intimal hyperplasia formation, pointing to Kv1.3 channels as promising therapeutical targets against restenosis.