Diabetic cardiac
fibrosis increases ventricular stiffness and facilitates the occurrence of diastolic dysfunction.
Retinoid X receptor (RXR) plays an important role in cardiac development and has been implicated in
cardiovascular diseases. In the present study, we investigated the effects of RXR agonist treatment on
streptozotocin (STZ)-induced
diabetic cardiomyopathy (DCM) and the underlying mechanism. Sprague-Dawley (SD) rats induced by STZ injection were treated with either RXR agonist
bexarotene (Bex) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with high
glucose (HG) with or without the indicated concentration of Bex or the RXR
ligand 9-cis-retinoic acid (9-cis-RA). The
protein abundance levels were measured along with
collagen,
body weight (BW), blood biochemical indexes and
transforming growth factor-β (TGF-β) levels. The effects of RXRα down-regulation by RXRα
small interfering RNA (
siRNA) were examined. The results showed that
bexarotene treatment resulted in amelioration of
left ventricular dysfunction by inhibiting cardiomyocyte apoptosis and myocardial
fibrosis. Immunoblot with heart tissue homogenates from diabetic rats revealed that
bexarotene activated liver
kinase B1 (LKB1) signaling and inhibited p70
ribosomal protein S6 kinase (
p70S6K). The increased
collagen levels in the heart tissues of DCM rats were reduced by
bexarotene treatment. Treatment of CFs with HG resulted in significantly reduced LKB1 activity and increased
p70S6K activity. RXRα mediated the antagonism of 9-cis-RA on HG-induced LKB1/
p70S6K activation changes in vitro. Our findings suggest that RXR agonist ameliorates STZ-induced DCM by inhibiting myocardial
fibrosis via modulation of the LKB1/
p70S6K signaling pathway. RXR agonists may serve as novel therapeutic agents for the treatment of DCM.