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Differential Effects of Hydrophilic versus Lipophilic Statins on RhoA Kinase Inhibition and Membrane Stability in Cardiac Myocytes
Author(s) -
Godoy Joseph,
Schilling Jan,
Schwarz Anna,
Asfaw Elizabeth,
Alvarez Erika,
Dalton Nancy,
Patel Hemal,
ZemljicHarpf Alice
Publication year - 2015
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.29.1_supplement.801.5
Subject(s) - pravastatin , rhoa , pitavastatin , atorvastatin , rosuvastatin , statin , pharmacology , fluvastatin , simvastatin , chemistry , protein kinase b , hmg coa reductase , medicine , cholesterol , biochemistry , signal transduction , reductase , enzyme
Statins are among the most prescribed drugs worldwide. By inhibiting mevalonate synthesis statins inhibit protein prenylation and thereby may reduce RhoA kinase activity. Cardiac overexpression of active RhoA was shown to be protective against ischemia reperfusion injury and membrane damage. We investigated effects of chemically different statins on RhoA kinase inhibition in cardiac myocytes (CM). Neonatal mouse CM were treated with simvastatin, pitavastatin, atorvastatin, rosuvastatin, or pravastatin and compared to vehicle. After 48hs only lipophilic and not hydrophilic statins, induced LDH release into the CM media (simvastatin > pitavastatin > atrovastatin, vehicle = pravastatin = rosuvastatin). Atorvastatin, but not pravastatin, reduced RhoA kinase activation in CM, and reduced protein expression of dystrophin, caveolin‐1, EGFR, and insulin receptor‐β. To test statin effects on the intact heart, wild type mice and cardiomyocyte specific vinculin knockout mice (cVclKO) were treated with atorvastatin, pravastatin, or vehicle for up to 7 months. Atorvastatin increased mortality in cVclKO mice that are prone to arrhythmias and heart failure compared to pravastatin or vehicle treated littermates. This is the first report showing differential effects of hydrophilic and lipophilic statin drugs on RhoA kinase inhibition, structural protein expression, and injury in CM.