RT info:eu-repo/semantics/article
T1 Myocardin-Dependent Kv1.5 Channel Expression Prevents Phenotypic Modulation of Human Vessels in Organ Culture
A1 Arévalo Martínez, Marycarmen
A1 Cidad Velasco, María del Pilar
A1 García Mateo, Nadia
A1 Moreno Estar, Sara
A1 Serna Pérez, Julia
A1 Fernández, Mirella
A1 Swärd, Karl
A1 Simarro Grande, María
A1 Fuente García, Miguel Ángel de la
A1 López López, José Ramón
A1 Pérez García, María Teresa
K1 Kv1 channels, phenotypic modulation, vascular smooth muscle, remodeling
AB Objective: We have previously described that changes in the expression of Kv channels associate to phenotypic modulation (PM), so that Kv1.3 /Kv1.5 ratio is a landmark of vascular smooth muscle cells (VSMCs) phenotype. Moreover, we demonstrated that the Kv1.3 functional expression is relevant for PM in several types of vascular lesions. Here, we explore the efficacy of Kv1.3 inhibition for the prevention of remodeling in human vessels, and the mechanisms linking the switch in Kv1.3 /Kv1.5 ratio to PM.Approach and Results: Vascular remodeling was explored using organ culture and primary cultures of VSMCs obtained from human vessels. We studied the effects of Kv1.3 inhibition on serum-induced remodeling, as well as the impact of viral vector-mediated overexpression of Kv channels or myocardin knock-down. Kv1.3 blockade prevented remodeling by inhibiting proliferation, migration and extracellular matrix (ECM) secretion. PM activated Kv1.3 via downregulation of Kv1.5. Hence, both Kv1.3 blockers and Kv1.5 overexpression inhibited remodeling in a non-additive fashion. Finally, myocardin knock-down induced vessel remodeling and Kv1.5 downregulation and myocardin overexpression increased Kv1.5, while Kv1.5 overexpression inhibited PM without changing myocardin expression. Conclusions: We demonstrate that Kv1.5 channel gene is a myocardin-regulated, VSMCs contractile marker. Kv1.5 downregulation upon PM leaves Kv1.3 as the dominant Kv1 channel expressed in dedifferentiated cells. We demonstrated that the inhibition of Kv1.3 channel function with selective blockers or by preventing Kv1.5 downregulation can represent an effective, novel strategy for the prevention of intimal hyperplasia and restenosis of the human vessels used for coronary angioplasty procedures.
SN 1079-5642
YR 2019
FD 2019
LK http://uvadoc.uva.es/handle/10324/39005
UL http://uvadoc.uva.es/handle/10324/39005
LA spa
NO Arterioscler Thromb Vasc Biol. 2019 Oct 10:ATVBAHA119313492. doi: 10.1161/ATVBAHA.119.313492
DS UVaDOC
RD 19-sep-2024