Abstract 271: Deletion of Delta-like 1 Homolog Accelerates Fibroblast-myofibroblast Differentiation and Induces Myocardial Fibrosis

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Luca Troncone ◽  
Patricia Rodriguez ◽  
Yassine Sassi ◽  
Ludovic Benard ◽  
Kiyotake Ishikawa ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Transmembrane Protein ◽  
Smooth Muscle Actin ◽  
Cardiac Fibroblast ◽  
Myofibroblast Differentiation ◽  
Potential Candidate ◽  
Smad 3

Myocardial fibrosis is associated with profound changes in ventricular architecture and geometry, resulting in diminished cardiac function. Here we uncover that Delta-like homologue 1 (Dlk1), a paternally imprinted gene encoding a transmembrane protein belonging to the Epidermal Growth Factor (EGF)-like family, orchestrates the process of cardiac fibroblast to myofibroblast differentiation and controls myocardial fibrosis. We first show that cardiomyocytes and cardiac fibroblasts express different Dlk1 mRNA spliced variants and its absence accelerates fibroblast differentiation into myofibroblasts in vitro. Overexpression of Dlk1 in cardiac fibroblasts resulted in inhibition of fibroblast proliferation and differentiation into myofibroblasts. This process appears to be regulated by TGFβ-1 signaling, since fibroblasts lacking Dlk1 exhibited a higher activation of the TGFβ-1/Smad-3 pathway at baseline, leading to an earlier acquisition of the myofibroblast phenotype. Dlk1-null mice myocardium displayed increased TGFβ-1/Smad3 profibrotic activity, resulting in infiltration/accumulation of myofibroblasts, and induction and deposition of the extracellular matrix fibronectin extra domain A isoform and collagen, supporting a role for Dlk1 in cardiac fibrosis. Furthermore, these profibrotic events were associated with reduced myofibril integrity, myocyte hypertrophy and cardiac dysfunction. Interestingly, Dlk1 expression was downregulated in ischemic heart tissue from human patients and in the border and scar-zones of infarcted pigs’ hearts. This phenotype was paralleled by increased expression of the profibrotic markers, collagen I, lysyl oxidase and α-smooth muscle actin. Mechanistically, the inhibitory action of Dlk1 on cardiac fibroblast-myofibroblast differentiation is mediated by miR-370 direct targeting of TGFβ-R2/Smad-3 signaling in the myocardium. Given the deleterious effects of continuous activation of this pathway, we propose Dlk1 as a new potential candidate for therapy in cases where aberrant TGFβ signaling leads to chronic fibrosis.

scholarly journals The Functional Role of Zinc Finger E Box-Binding Homeobox 2 (Zeb2) in Promoting Cardiac Fibroblast Activation

2018 ◽  
Vol 19 (10) ◽  
pp. 3207 ◽  
Author(s):  
Fahmida Jahan ◽  
Natalie Landry ◽  
Sunil Rattan ◽  
Ian Dixon ◽  
Jeffrey Wigle
Keyword(s):  
Smooth Muscle ◽  
Zinc Finger ◽  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Critical Role ◽  
Cardiac Fibroblast ◽  
In Vivo Studies ◽  
Fibroblast Activation ◽  
E Box

Following cardiac injury, fibroblasts are activated and are termed as myofibroblasts, and these cells are key players in extracellular matrix (ECM) remodeling and fibrosis, itself a primary contributor to heart failure. Nutraceuticals have been shown to blunt cardiac fibrosis in both in-vitro and in-vivo studies. However, nutraceuticals have had conflicting results in clinical trials, and there are no effective therapies currently available to specifically target cardiac fibrosis. We have previously shown that expression of the zinc finger E box-binding homeobox 2 (Zeb2) transcription factor increases as fibroblasts are activated. We now show that Zeb2 plays a critical role in fibroblast activation. Zeb2 overexpression in primary rat cardiac fibroblasts is associated with significantly increased expression of embryonic smooth muscle myosin heavy chain (SMemb), ED-A fibronectin and α-smooth muscle actin (α-SMA). We found that Zeb2 was highly expressed in activated myofibroblast nuclei but not in the nuclei of inactive fibroblasts. Moreover, ectopic Zeb2 expression in myofibroblasts resulted in a significantly less migratory phenotype with elevated contractility, which are characteristics of mature myofibroblasts. Knockdown of Zeb2 with siRNA in primary myofibroblasts did not alter the expression of myofibroblast markers, which may indicate that Zeb2 is functionally redundant with other profibrotic transcription factors. These findings add to our understanding of the contribution of Zeb2 to the mechanisms controlling cardiac fibroblast activation.

Abstract 15671: Adipocyte-derived Exosomal Lncrna Nbr2 Promotes Diabetic Myocardial Fibrosis Through Regulating the Ikba/nf-kb Pathway

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yue Guo ◽  
Xingfeng Xu ◽  
Lingling Wu ◽  
Xiaodong Zhuang ◽  
Xinxue Liao
Keyword(s):  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Epigenetic Mechanism ◽  
Ang Ii ◽  
Intramyocardial Injection ◽  
Underlying Mechanisms ◽  
Human Cardiac Fibroblasts ◽  
And Function

Introduction: The activation of NF-κB is the dominant process that correlates with the pathogenesis of diabetic cardiomyopathy (DCM). Recently, accumulating evidence shows that long noncoding RNAs (lncRNAs) play crucial roles in sustaining the NF-κB pathway. However, the underlying mechanisms remain unclear. In this study, we identified the upregulated expressed lncRNA NBR2 in adipocyte-derived exosomes (AdEXO) and investigated its regulatory role in diabetic myocardial fibrosis. Hypothesis: We hypothesized that AdEXO-NBR2 promotes diabetic myocardial fibrosis through regulating the IκBα/NF-κB pathway. Methods: We examined the effect of exosomes from diabetic (db/db) mice-derived adipocytes on ANG-II-induced cardiac fibrosis and function in non-diabetic (C57BL/6J mice). In the invitro study, HG (33mmol/L)-stimulated AdEXO were cultured with adult human cardiac fibroblasts (aHCFs). Differentially expressed lncRNAs in AdEXO were screened using lncRNA sequencing. Results: Intramyocardial injection of diabetic AdEXO in the non-diabetic heart significantly exacerbated myocardial fibrosis, as evidenced by poorer cardiac function and enhancer collagen deposition. Whereas administration of a exosomes biogenesis inhibitor mitigated cardiac fibrosis in diabetic mice. We found lncRNA-NBR2 is a common molecule significantly increased in diabetic AdEXO and HG-stimulated non-diabetic AdEXO. After four weeks of ANG II infusion, EXO-db/dbWT-injected mice displayed fibrosis in the heart. However, interestingly, mice receiving NBR2-deficient db/db-EXO showed a decrease in cardiac fibrosis. Similarly, AdEXO-NBR2 promoted aHCFs proliferation and transformation capabilities in vitro. Mechanistically, NBR2 was loaded to AdEXO by directly interacting with heterogeneous nuclear ribonucleoprotein K (hnRNPK). Subsequently, AdEXO-NBR2 was internalized by aHCFs and epigenetically downregulated IκBα expression by recruitment of hnRNPK/SETDB1 and increasing the H3K9 trimethylation level in the IκBα promoter, ultimately activating the NF-κB pathway. Conclusions: Our findings highlight a novel epigenetic mechanism of AdEXO lncRNA-mediated diabetic cardiac fibrosis and identify NBR2 as a therapeutic target of DCM.

Abstract P107: Hypertension Enhances the Differentiation of Cardiac Fibroblasts Into Myofibroblasts After TGF-beta1 Treatment

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Gianluca L Perrucci ◽  
Maria Corlian!ò ◽  
Delfina Tosi ◽  
Patrizia Nigro ◽  
Gaetano Bulfamante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Pcr Analysis ◽  
Alpha Smooth Muscle Actin ◽  
Qrt Pcr ◽  
Gene And Protein Expression

Objectives: In cardiac fibrosis associated with hypertension, TGF-beta1 plays a key role by acting on differentiation of cardiac fibroblasts (CF) into alpha-smooth muscle actin (alpha-SMA)-positive myofibroblasts. In this study, we tested the effect of TGF-beta1 during the myofibroblast differentiation process of CF from normotensive and hypertensive rats. Methods: CF were obtained by enzymatic digestion of hearts isolated from Spontaneously Hypertensive (hCF) and normotensive Wistar Kyoto (nCF) rats (n=5 rat/group). Gene and protein expression in CF was evaluated by Western blot and qRT-PCR analyses, respectively. Immunohistochemistry analysis for integrin alpha-v beta-5 was performed on rat cardiac tissue (n=5 rat/group). Results: Cultured hCF showed an enhanced SMAD2/3 activation and alpha-SMA protein expression after treatment with TGF-beta1 (5 ng/ml) in comparison with nCF. Alpha-SMA up-regulation was further confirmed by qRT-PCR analysis that showed a significant increase in alpha-SMA gene expression in hCF after TGF-beta1 treatment (2.78±0.25 vs 2.01±0.21 fold increase, p <0.05). Moreover, immunostaining on cardiac tissues revealed a higher expression of integrin alpha-v beta-5 in hypertensive vs normotensive rat hearts (345.3±170.0 vs 48.2±22.3 mm 2 of integrin-positive area, p <0.05). This result was also confirmed in vitro ; indeed, integrin alpha-v beta-5 gene expression in hCF increased 2.8-fold in basal condition and 5.12-fold after TGF-beta1 treatment when compared to untreated nCF. Conclusions: Taken together, these results suggest that hCF are more prone to upregulate integrin alpha-v beta-5 and consequently differentiate into myofibroblasts in vitro under TGF-beta1 treatment. Thus, targeting alpha-v beta-5 might open a novel prospective for the treatment of fibrosis in hypertensive hearts likely reducing integrin-mediated TGF-beta1 activation.

scholarly journals Celastrol-Induced Suppression of the MiR-21/ERK Signalling Pathway Attenuates Cardiac Fibrosis and Dysfunction

2016 ◽  
Vol 38 (5) ◽  
pp. 1928-1938 ◽  
Author(s):  
Mian Cheng ◽  
Gang Wu ◽  
Yue Song ◽  
Lin Wang ◽  
Ling Tu ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Signalling Pathway ◽  
Tgf Β1

Backgroud: Myocardial fibrosis results in myocardial remodelling and dysfunction. Celastrol, a traditional oriental medicine, has been suggested to have cardioprotective effects. However, its underlying mechanism is unknown. This study investigated the ability of celastrol to prevent cardiac fibrosis and dysfunction and explored the underlying mechanisms. Methods: Animal and cell models of cardiac fibrosis were used in this study. Myocardial fibrosis was induced by transverse aortic constriction (TAC) in mice. Cardiac hypertrophy and fibrosis were evaluated based on histological and biochemical measurements. Cardiac function was evaluated by echocardiography. The levels of transforming growth factor beta 1 (TGF-β1), extracellular signal regulated kinases 1/2 (ERK1/2) signalling were measured using Western blotting, while the expression of miR-21was analyzed by real-time qRT-PCR in vitro and in vivo. In vitro studies, cultured cardiac fibroblasts (CFs) were treated with TGF-β1 and transfected with microRNA-21(miR21). Results: Celastrol treatment reduced the increased collagen deposition and down-regulated α-smooth muscle actin (α-SMA), atrial natriuretic peptide (ANP), brain natriuretic peptides (BNP), beta-myosin heavy chain (β-MHC), miR-21 and p-ERK/ERK. Cardiac dysfunction was significantly attenuated by celastrol treatment in the TAC mice model. Celastrol treatment reduced myocardial fibroblast viability and collagen content and down-regulated α-SMA in cultured CFs in vitro. Celastrol also inhibited the miR-21/ERK signalling pathway. Celastrol attenuated miR-21 up-regulation by TGF-β1 and decreased elevated p-ERK/ERK levels in CFs transfected with miR-21. Conclusion: MiR-21/ERK signalling could be a potential therapeutic pathway for the prevention of myocardial fibrosis. Celastrol ameliorates myocardial fibrosis and cardiac dysfunction, these probably related to miR-21/ERK signaling pathways in vitro and in vivo.

scholarly journals Calcitriol Attenuates Doxorubicin-Induced Cardiac Dysfunction and Inhibits Endothelial-to-Mesenchymal Transition in Mice

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 865 ◽  
Author(s):  
Tsai ◽  
Lin ◽  
Hang ◽  
Chen
Keyword(s):  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Umbilical Vein ◽  
Active Form ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition ◽  
Umbilical Vein Endothelial Cells

Doxorubicin (Dox) is an effective anti-neoplasm drug, but its cardiac toxicity limits its clinical use. Endothelial-to-mesenchymal transition (EndMT) has been found to be involved in the process of heart failure. It is unclear whether EndMT contributes to Dox-induced cardiomyopathy (DoIC). Calcitriol, an active form Vitamin D3, blocks the growth of cancer cells by inhibiting the Smad pathway. To investigate the effect of calcitriol via inhibiting EndMT in DoIC, C57BL/6 mice and endothelial-specific labeled mice were intraperitoneally administered Dox twice weekly for 4 weeks (32 mg/kg cumulative dose) and were subsequently treated with or without calcitriol for 12 weeks. Echocardiography revealed diastolic dysfunction at 13 weeks following the first Dox treatment, accompanied by increased myocardial fibrosis and up-regulated pro-fibrotic proteins. Calcitriol attenuated Dox-induced myocardial fibrosis, down-regulated pro-fibrotic proteins and improved diastolic function. Endothelial fate tracing revealed that EndMT-derived cells contributed to Dox-induced cardiac fibrosis. In vitro, human umbilical vein endothelial cells and mouse cardiac fibroblasts were treated with Transforming growth factor (TGF)-β with or without calcitriol. Morphological, immunofluorescence staining, and Western blot analyses revealed that TGF-β-induced EndMT and fibroblast-to-myofibroblast transition (FMT) were attenuated by calcitriol by the inhibition of the Smad2 pathway. Collectively, calcitriol attenuated DoIC through the inhibition of the EndMT and FMT processes.

scholarly journals Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Qiankun Bao ◽  
Bangying Zhang ◽  
Ya Suo ◽  
Chen Liu ◽  
Qian Yang ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Cardiac Fibrosis ◽  
Synergistic Effects ◽  
Cardiac Fibroblasts ◽  
Cardiac Fibroblast ◽  
Ang Ii ◽  
Fibroblast Activation ◽  
Obstructive Sleep

Intermittent hypoxia (IH) is the predominant pathophysiological disturbance in obstructive sleep apnea (OSA), known to be independently associated with cardiovascular diseases. However, the effect of IH on cardiac fibrosis and molecular events involved in this process are unclear. Here, we tested IH in angiotensin II (Ang II)-induced cardiac fibrosis and signaling linked to fibroblast activation. IH triggered cardiac fibrosis and aggravated Ang II-induced cardiac dysfunction in mice. Plasma thrombospondin-1 (TSP1) content was upregulated in both IH-exposed mice and OSA patients. Moreover, both in vivo and in vitro results showed IH-induced cardiac fibroblast activation and increased TSP1 expression in cardiac fibroblasts. Mechanistically, phosphorylation of STAT3 at Tyr705 mediated the IH-induced TSP1 expression and fibroblast activation. Finally, STAT3 inhibitor S3I-201 or AAV9 carrying a periostin promoter driving the expression of shRNA targeting Stat3 significantly attenuated the synergistic effects of IH and Ang II on cardiac fibrosis in mice. This work suggests a potential therapeutic strategy for OSA-related fibrotic heart disease.

Abstract 305: E2F1 Suppresses Cardiac Fibrosis

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Dauren Biyashev ◽  
Chan Boriboun ◽  
Gangjian Qin
Keyword(s):  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Mouse Heart ◽  
Wild Type ◽  
Alpha Smooth Muscle Actin ◽  
Embryonic Fibroblasts ◽  
Smad 3 ◽  
Regulation Of Cell Cycle

E2F1 transcription factor is best known for regulation of cell cycle; its role in the cardiovascular system is not well understood. In a transcriptome analysis, we detected a significantly elevated level in the expression of collagen I and alpha-smooth muscle actin in the E2F1-null (E2F1-/-) mouse embryonic fibroblasts (MEFs) as compared to wild-type (WT) MEFs. Levels of Smad 2 and Smad 3 were also significantly higher in E2F1-/- MEFs. In addition, treatment with TGF-beta (10 ng/ml) induced a greater degree of Smad 2 and Smad 3 phosphorylation in E2F1-/- MEFs than in WT MEFs. Interestingly, these in vitro observations were corroborated with our results obtained from mouse heart samples: the basal levels of both total and phosphorylated Smad 2 were significantly higher in the E2F1-/- heart than in the WT heart (n=3). To understand the significance of these findings in the pathogenesis of cardiac fibrosis, we administered Angiotensin II (3 mg/kg/day) to animals for 7 or 14 days with a subcutaneous osmotic minipump. The total area of cardiac fibrosis was significantly greater in the E2F1-/- mice than in WT littermates (E2F1-/- vs. WT: 17+/-3.8% vs. 6+/-2.6%, p<0.05). Thus, we disclose a novel role of E2F1 in the control of Smad signaling that may limit the development of fibrosis in the stressed heart.

Persistent change in cardiac fibroblast physiology after transient ACE inhibition

2015 ◽  
Vol 309 (8) ◽  
pp. H1346-H1353 ◽  
Author(s):  
K. M. D'Souza ◽  
L. A. Biwer ◽  
L. Madhavpeddi ◽  
P. Ramaiah ◽  
W. Shahid ◽  
...  
Keyword(s):  
Methyl Ester ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Ace Inhibition ◽  
Cardiac Fibroblast ◽  
Type I ◽  
Monocyte Chemoattractant Protein 1 ◽  
Nos Inhibitor

Transient angiotensin-converting enzyme (ACE) inhibition induces persistent changes that protect against future nitric oxide synthase (NOS) inhibitor-induced cardiac fibrosis and inflammation. Given the role of fibroblasts in mediating these effects, the present study investigates whether prior ACE inhibition produced persistent changes in cardiac fibroblast physiology. Adult male spontaneously hypertensive rats (SHRs) were treated with vehicle (C+L) or the ACE inhibitor, enalapril (E+L) for 2 wk followed by a 2-wk washout period and a subsequent 7-day challenge with the NOS inhibitor Nω-nitro-l-arginine methyl ester. A third set of untreated SHRs served as controls. At the end of the study period, cardiac fibroblasts were isolated from control, C+L, and E+L left ventricles to assess proliferation rate, collagen expression, and chemokine release in vitro. After 7 days of NOS inhibition, there were areas of myocardial injury but no significant change in collagen deposition in E+L and C+L hearts in vivo. In vitro, cardiac fibroblasts isolated from C+L but not E+L hearts were hyperproliferative, demonstrated increased collagen type I gene expression, and an elevated secretion of the macrophage-recruiting chemokines monocyte chemoattractant protein-1 and granulocyte macrophage-colony stimulating factor. These findings demonstrate that in vivo Nω-nitro-l-arginine methyl ester treatment produces phenotypic changes in fibroblasts that persist in vitro. Moreover, this is the first demonstration that transient ACE inhibition can produce a persistent modification of the cardiac fibroblast phenotype to one that is less inflammatory and fibrogenic. It may be that the cardioprotective effects of ACE inhibition are related in part to beneficial changes in cardiac fibroblast physiology.

Abstract P475: Microrna-129-5p Rescues Myocardial Fibrosis And Calcification By Targeting Asporin And Sox9 In Cardiac Fibroblasts

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Lejla Medzikovic ◽  
Laila Aryan ◽  
Gregoire Ruffenach ◽  
Min Li ◽  
Nicoletta Savalli ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Systolic Dysfunction ◽  
Transforming Growth Factor Β ◽  
Calcium Deposition ◽  
Systemic Delivery ◽  
Myocardial Calcification

Myocardial fibrosis promotes heart failure (HF) progression by impairing myocardial compliance, but also may predispose to myocardial calcification, further impairing cardiac function. Transition of resident cardiac fibroblast (CF) to pro-fibrotic myofibroblasts (MF) and osteogenic cell fates (OF) are key events which are partially controlled by microRNAs (miRs). To discover novel miRs involved in myocardial fibrosis and calcification, we compared online-available microarray datasets of left ventricles (LV) from failing human and mouse hearts. Assessing differentially-expressed miRs known to regulate fibrosis and calcification genes revealed that miR-129-5p is significantly downregulated in HF LV. Bioinformatic target analysis revealed small leucin-rich proteoglycan Asporin (Aspn) and SRY-Box Transcription Factor 9 (Sox9) as two novel miR-129-5p targets upregulated in both mouse and human diseased LV. Thus far, nothing is known about miR-129-5p in cardiac fibrosis and calcification. Additionally, the role of Asporin in myocardial fibrosis and the roles of either Asporin or Sox9 in myocardial calcification remain undiscovered. We show that miR-129-5p is expressed in CF in mouse and human hearts and is downregulated in CF of both HF patients and Angiotensin II (AngII)-injured mice, while Asporin and Sox9 are upregulated in CF of HF LV. In vitro , AngII or transforming growth factor-β downregulated miR-129-5p expression in primary adult mouse CF. Overexpression of miR-129-5p in CF inhibited expression of MF and OF transition markers, reduced migration, collagen production and calcium deposition. We validated Asporin and Sox9 as direct targets of miR-129-5p. Accordingly, silencing of Asporin and Sox9 in CF attenuated molecular and functional characteristics of MF and OF transition. Strikingly, systemic delivery of miR-129-5p mimics in mice directly targets CF and is sufficient to rescue preexisting AngII-induced myocardial fibrosis, calcification, diastolic- and systolic dysfunction. In conclusion, miR-129-5p rescues myocardial fibrosis and calcification by attenuating MF and OF transition via inhibition of Asporin and Sox9 in CF and is a promising therapeutic target.

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

2020 ◽  
Vol 134 (6) ◽  
pp. 609-628 ◽  
Author(s):  
Dajun Chai ◽  
Xiaoyan Lin ◽  
Qiaowen Zheng ◽  
Changsheng Xu ◽  
Hong Xie ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Transforming Growth Factor Β ◽  
Underlying Mechanism ◽  
Left Ventricular ◽  
Retinoid X Receptor ◽  
Sprague Dawley

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.

Sign in / Sign up

Export Citation Format

Share Document