Retinoid X receptor agonists attenuates cardiomyopathy in streptozotocin-induced type 1 diabetes through LKB1-dependent anti-fibrosis effects

Abstract

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.

Dapagliflozin: a sodium–glucose cotransporter 2 inhibitor, attenuates angiotensin II-induced cardiac fibrotic remodeling by regulating TGFβ1/Smad signaling

“…Images were quantified and analyzed by the Echopack 113.1.3 image analysis system (GE Healthcare). End-diastolic interventricular septum thickness (IVSd), end-diastolic left ventricular posterior wall thickness (LVPWd), and end-diastolic and end-systolic left ventricular internal diameters (LVIDd and LVIDs) were measured, and the left ventricular fractional shortening (LVFS) and the left ventricular ejection fraction (LVEF) were calculated as described previously [ 16 ].…”

“…Primary cardiac fibroblasts (CFs) isolated from adult rat ventricular tissues as previously described [ 16 ]. Briefly, cells were grown in M199 medium (HyClone, Cat no: SH30253.01) (10% fetal bovine serum and 1% penicillin/streptomycin) at 5% CO 2 , 37 °C incubator.…”

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

“…Interestingly, excessive levels of vitamin A during development is teratogenic and can also increase the risk of congenital heart disease [104,105]. RAR or RXR agonists prevent cardiomyocyte apoptosis and cardiac fibrosis induced by hyperglycemia in rat cardiomyocytes [106] via activating liver kinase B1 (LKB1) signaling and inhibiting p70 ribosomal protein S6 kinase activity (p70S6K) [107]. LKB1 is a key player in metabolic regulation through activation of AMPK, which can in turn inhibit the mTOR signaling pathway, and p70S6K is immediately downstream of mTOR complex 1 (mTORC1) [108].…”

Dapagliflozin: a Sodium-glucose Cotransporter 2 Inhibitor, Attenuates Angiotensin II-induced Cardiac Fibrotic Remodeling by Regulating TGFβ1/ Smad Signaling

“…Primary cardiac broblasts (CFs) isolated from adult rat ventricular tissues as previously described [16]. Brie y, cells were grown in M199 medium (HyClone, Cat no: SH30253.01) (10 % fetal bovine serum and 1 % penicillin/streptomycin) at 5% CO 2 , 37°C incubator.…”

“…Images were quanti ed and analyzed by the Echopack 113.1.3 image analysis system (GE Healthcare). End-diastolic interventricular septum thickness (IVSd), end-diastolic left ventricular posterior wall thickness (LVPWd), and end-diastolic and end-systolic left ventricular internal diameters (LVIDd and LVIDs) were measured, and the left ventricular fractional shortening (LVFS) and the left ventricular ejection fraction (LVEF) were calculated as described previously [16]. The systolic peak velocities (s, s′), early diastolic peak velocities (e, e′) and end-diastolic peak velocities (a, a′) of the lateral and septal mitral annulus on the apical four-chamber view were measured using the quantitative tissue velocity imaging (QTVI) software (GE Healthcare).…”