TY - JOUR
T1 - Statin-specific inhibition of Rab-GTPase regulates cPKC-mediated IKs internalization
AU - Ronzier, Elsa
AU - Parks, Xiaorong Xu
AU - Qudsi, Haani
AU - Lopes, Coeli M.
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85075624081&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-53700-6
DO - 10.1038/s41598-019-53700-6
M3 - Article
C2 - 31780674
AN - SCOPUS:85075624081
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 17747
ER -