Statin-specific inhibition of Rab-GTPase regulates cPKC-mediated IKs internalization

Autor: Xiaorong Xu Parks, Coeli M. Lopes, Haani Qudsi, Elsa Ronzier
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Simvastatin
Statin
Physiology
medicine.drug_class
media_common.quotation_subject
Atorvastatin
Biophysics
Cardiology
lcsh:Medicine
030204 cardiovascular system & hematology
Pharmacology
Article
03 medical and health sciences
0302 clinical medicine
Prenylation
medicine
Animals
Humans
Myocytes
Cardiac
Rosuvastatin
cardiovascular diseases
Rosuvastatin Calcium
Fluvastatin
Internalization
lcsh:Science
Cells
Cultured
Protein Kinase C
media_common
Multidisciplinary
Molecular medicine
business.industry
lcsh:R
nutritional and metabolic diseases
Rats
3. Good health
HEK293 Cells
030104 developmental biology
Potassium Channels
Voltage-Gated
rab GTP-Binding Proteins
lipids (amino acids
peptides
and proteins)
lcsh:Q
Rab
Hydroxymethylglutaryl-CoA Reductase Inhibitors
business
medicine.drug
Zdroj: Scientific Reports, Vol 9, Iss 1, Pp 1-12 (2019)
Scientific Reports
ISSN: 2045-2322
DOI: 10.1038/s41598-019-53700-6
Popis: Statins are prescribed for prevention and treatment of coronary artery disease. Statins have different cholesterol lowering abilities, with rosuvastatin and atorvastatin being the most effective, while statins like simvastatin and fluvastatin having lower effectiveness. Statins, in addition to their cholesterol lowering effects, can prevent isoprenylation of Rab-GTPase proteins, a protein family important for the regulation of membrane-bound protein trafficking. Here we show that endosomal localization of Rab-GTPases (Rab5, Rab7 and Rab11) was inhibited in a statin-specific manner, with stronger effects by fluvastatin, followed by simvastatin and atorvastatin, and with a limited effect by rosuvastatin. Fluvastatin inhibition of Rab5 has been shown to mediate cPKC-dependent trafficking regulation of the cardiac delayed rectifier KCNQ1/KCNE1 channels. We observed statin-specific inhibition of channel regulation consistent with statin-specific Rab-GTPase inhibition both in heterologous systems and cardiomyocytes. Our results uncover a non-cholesterol-reducing statin-specific effect of statins. Because Rab-GTPases are important regulators of membrane trafficking they may underlie statin specific pleiotropic effects. Therefore, statin-specificity may allow better treatment tailoring.
Databáze: OpenAIRE
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