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Kv1.3 and Kv1.5 Channels as Novel Targets for the Prevention of Restenosis in Human Vessels
Author(s) -
PerezGarcia M Teresa,
ArevaloMartinez Marycarmen,
Fuente Miguel Angel,
Simarro Maria,
Alonso Esperanza,
LopezLopez José Ramón,
Cidad Pilar
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1015.4
Subject(s) - intimal hyperplasia , restenosis , vascular smooth muscle , organ culture , hyperplasia , microbiology and biotechnology , artery , downregulation and upregulation , neointimal hyperplasia , phenotype , blood vessel , medicine , biology , endocrinology , in vitro , smooth muscle , biochemistry , gene , stent
The contractile state of vascular smooth muscle cells (VSMCs) in the vessel media determines vascular tone. However, these cells can undergo a phenotypic modulation (PM) towards a synthetic phenotype in response to injury. Upon PM, VSMCs lose their contractile proteins and adquire proliferative, migratory and secretory skills. PM is central to the process of intimal hyperplasia that leads to restenosis of the vessel following vascular injury. We have previously described changes in the expression of Kv1.3 and Kv1.5 channels associated with PM. Proliferating VSMCs show an increased functional expression of Kv1.3 channels with a concomitant loss of Kv1.5 channels. Moreover, Kv1.3 blockers inhibit proliferation and migration in animal models of vascular injury and in VSMCs in primary cultures. In this work, we explored if this Kv1.5 to Kv1.3 swicth is also present in human vessels undergoing PM, and we investigate the underliying mechanisms linking Kv channel switch to the development of intimal hyperplasia. We explored PM in human mammary artery (hMA) samples using organ culture of arterial rings and primary culture of VSMCs from arterial explants. We tested the effect of Kv1.3 and Kv1.5 manipulations by overexpresion of Kv1.5 with viral vectors and blockade of Kv1.3 channels with the selective inhibitor PAP‐1. The degree of intimal hyperplasia in the organ culture was explored with hystomorphometric analyses. Changes in proliferation, migration and secretion were also studied in both preparations. Fetal Bovine Serum (FBS) treatment induced intimal hyperplasia leading to stenosis in organ culture, which was prevented with PAP‐1. PAP‐1 decreased both FBS‐induced proliferation and VSMCs secretion, as the increase in the number of elastic laminae induced by FBS was fully reverted in the presence of PAP‐1. Kv1.3 blockers also inhibited proliferation of hMA VSMCs in culture. In addition, overexpression of Kv1.5 channels had an antiproliferative effect that can be explained by Kv1.5 occlusion of Kv1.3 pro‐proliferative effects. We show that organ culture of human vessels represents a valuable approach for the study of the complex, multifactorial process of vascular restenosis. Many of these processes can be targeted by the use of PAP‐1, so that therapies using Kv1.3 blockers could represent a significant improvement for the prevention of intimal hyperplasia. Support or Funding Information Supported by grants ISCIII‐FEDER RD12/0042/0006, (Heracles Program), BFU2013‐45867‐R (MINECO) and by UVA‐Santander fellowship to MAM.