Myocardin-Dependent Kv1.5 Channel Expression Prevents Phenotypic Modulation of Human Vessels in Organ Culture
| Autor: | Pilar Cidad, Mirella Fernández, Sara Moreno-Estar, M. Teresa Pérez-García, Miguel Angel de la Fuente, José R. López-López, Nadia García-Mateo, Julia Serna, Marycarmen Arévalo-Martínez, María Simarro, Karl Swärd |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Junta de Castilla y León, Instituto de Salud Carlos III, Universidad de Valladolid, Banco Santander, Swedish Research Council |
| Jazyk: | Spanish; Castilian |
| Rok vydání: | 2019 |
| Předmět: |
Vascular smooth muscle
Phenotypic modulation Cell Coronary Artery Disease Vascular Remodeling Biology Organ culture complex mixtures Muscle Smooth Vascular Article Kv channel Extracellular matrix Kv1.5 Potassium Channel Organ Culture Techniques Downregulation and upregulation medicine Humans natural sciences Cells Cultured Kv1 channels phenotypic modulation vascular smooth muscle remodeling Kv1.3 Potassium Channel urogenital system Nuclear Proteins Coronary Vessels Immunohistochemistry Cell biology Phenotype medicine.anatomical_structure Gene Expression Regulation nervous system Myocardin Trans-Activators RNA biological phenomena cell phenomena and immunity Cardiology and Cardiovascular Medicine |
| Zdroj: | UVaDOC. Repositorio Documental de la Universidad de Valladolid instname Arterioscler Thromb Vasc Biol Digital.CSIC. Repositorio Institucional del CSIC |
| Popis: | [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 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 vascular smooth muscle cells 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 secretion. PM activated Kv1.3 via downregulation of Kv1.5. Hence, both Kv1.3 blockers and Kv1.5 overexpression inhibited remodeling in a nonadditive 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, vascular smooth muscle cells 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. This work was supported by grant BFU2016-75360-R from the Ministerio de Economía y Competitividad (MINECO), to M.T. Pérez-García and J.R. López-López and Junta de Castilla y León Grant VA114P17 to M.T. Pérez-García. N. García-Mateo was supported by FIS PI15/00064 from the Instituto de Salud Carlos III. M. Arévalo-Martínez and J. Serna are predoctoral fellows of the UVa-Santander, and S. Moreno-Estar is a predoctoral fellow of the JCyL. K. Swärd was supported by the Swedish Research Council (2017-01225_3). |
| Databáze: | OpenAIRE |
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