Inhibition of NF-κB and Wnt/β-catenin/GSK3β Signaling Pathways Ameliorates Cardiomyocyte Hypertrophy and Fibrosis in Streptozotocin (STZ)-induced Type 1 Diabetic Rats

Abstract

Type 1 diabetes mellitus (T1DM) is associated with an increased risk of diabetic cardiomyopathy (DCM). Nuclear factor kappa B (NF-κB) and Wnt/β-catenin/GSK3β have been demonstrated to play pathogenic roles in diabetes. In this study, we evaluated the roles of these two pathways in T1DM-induced cardiomyopathy in rats. Streptozotocin (STZ)-induced type 1 diabetic rats were treated with pyrrolidine dithiocarbamate (PDTC) or meisoindigo (Me) to inhibit NF-κB and Wnt/β-catenm/GSK3β respectively for 4 or 8 weeks. As compared with untreated diabetic rats, treatment with either PDTC or Me partly attenuated the myocardial hypertrophy and interstitial fibrosis, improved cardiac function, and exhibited reduction in inflammatory reaction. In addition, we found that inhibiting NF-κB and Wnt/β-catenin/GSK3β pathways could regulate glucose and lipid metabolism. The effects were associated with the decrease of NF-κB activity and the downregulation of some proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-2. Our data suggested that the activities of NF-κB and Wnt/β-catenin/GSK3β pathways were both increased and inhibiting NF-κB and Wnt/β-catenin/GSK3β signaling pathways might improve myocardial injury in T1DM rats.

Keywords

type 1 diabetes mellitus / diabetic cardiomyopathy / NF-κB / Wnt/β-catenin/GSK3β

References

[1] ZhangZ, ZhangD, DouM, et al.. Dendrobium officinale Kimura et Migo attenuates diabetic cardiomyopathy through inhibiting oxidative stress, inflammation and fibrosis in streptozotocin-induced mice. Biomed Pharmacother, 2016, 84: 1350-1358

[2] LiuQ, WangS, CaiL. Diabetic cardiomyopathy and its mechanisms: Role of oxidative stress and damage. J Diabetes Invest, 2015, 5(6): 623-634

[3] van DiepenJA, ThiemK, StienstraR, et al.. Diabetes propels the risk for cardiovascular disease: sweet monocytes becoming aggressive. Cell Mol Life Sci, 2016, 73(24): 4675

[4] WanA, RodriguesB. Endothelial cell-cardiomyocyte crosstalk in diabetic cardiomyopathy. Cardiovasc Res, 2016, 111: 172-183

[5] RajeshM, MukhopadhyayP, BátkaiS, et al.. Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol, 2010, 56(25): 2115-2125

[6] GuoR, NairS. Role of microRNA in diabetic cardiomyopathy: From mechanism to intervention. Biochim Biophys Acta, 2017, 1863: 2070-2077

[7] ZhengX, ZhuS, ChangS, et al.. Protective effects of chronic resveratrol treatment on vascular inflammatory injury in streptozotocin-induced type 2 diabetic rats: Role of NF-kappa B signaling. Eur J Pharmacol, 2013, 720(1–3): 147-157

[8] MongM, YinM. Nuclear Factor κB-Dependent Anti-inflammatory Effects of s-Allyl Cysteine and s-Propyl Cysteine in Kidney of Diabetic Mice. J Agric Food Chem, 2012, 60(12): 3158-3165

[9] El-SaharAE, SafarMM, ZakiHF, et al.. Neuroprotective effects of pioglitazone against transient cerebral ischemic reperfusion injury in diabetic rats: Modulation of antioxidant, anti-inflammatory, and anti-apoptotic biomarkers. Pharmacol Rep, 2015, 67(5): 901-906

[10] ElçioğluHK, KabasakalL, ÖzkanN, et al.. A study comparing the effects of rosiglitazone and/or insulin treatments on streptozotocin induced diabetic (type I diabetes) rat aorta and cavernous tissues. Eur J Pharmacol, 2011, 660(2–3): 476-484

[11] GoudyKS, JohnsonMC, GarlandA, et al.. Inducible adeno-associated virus-mediated IL-2 gene therapy prevents autoimmune diabetes. J Immunol, 2011, 186(6): 3779-3786

[12] DawsonK, AflakiM, NattelS. Role of the Wnt-Frizzled system in cardiac pathophysiology: a rapidly developing, poorly understood area with enormous potential. J Physiol, 2013, 591(6): 1409-1432

[13] ChongZZ, MaieseK. Targeting WNT. Protein kinase B, and mitochondrial membrane integrity to foster cellular survival in the nervous system. Histol Histopathol, 2004, 19(2): 495-504

[14] HieM, IitsukaN, OtsukaT, et al.. Insulin-dependent diabetes mellitus decreases osteoblastogenesis associated with the inhibition of Wnt signaling through increased expression of Sost and Dkk1 and inhibition of Akt activation. Int J Mol Med, 2011, 28(3): 455-462

[15] ErenG, CukurovaZ, HergunselO, et al.. Protective effect of the nuclear factor kappa B inhibitor pyrrolidine dithiocarbamate in lung injury in rats with streptozotocin-induced diabetes. Respiration, 2010, 79(5): 402-410

[16] HuangM, HoPC. Identification of metabolites of meisoindigo in rat, pig and human liver microsomes by UFLC-MS/MS. Biochem Pharmacol, 2009, 77(8): 1418-1428

[17] ZhuYF, YeBG, ShenJZ, et al.. Inhibitory effect of VPA on multiple myeloma U266 cell proliferation and regulation of histone acetylation. Zhongguo Shi Yan Xue Ye Xue Za Zhi (Chinese), 2010, 18(3): 638-641

[18] ShengR, GuZL, XieML. Epigallocatechin gallate, the major component of polyphenols in green tea, inhibits telomere attrition mediated cardiomyocyte apoptosis in cardiac hypertrophy. Int J Cardiol, 2013, 162(3): 199-209

[19] WeiH, QuH, WangH, et al.. 1,25-Dihydroxyvitamin-D3 prevents the development of diabetic cardiomyopathy in type 1 diabetic rats by enhancing autophagy via inhibiting the β-catenin/TCF4/GSK-3β/mTOR pathway. J Steroid Biochem Mol Biol, 2017, 168: 71-90

[20] TsaiSJ, HuangCS, MongMC, et al.. Anti-inflammatory and antifibrotic effects of naringenin in diabetic mice. J Agric Food Chem, 2012, 60(1): 514-521

[21] MartinezA, CastroA, DorronsoroI, et al.. Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Med Res Rev, 2002, 22(4): 373-384

[22] Monika, SharmaA, SutharSK, et al.. Synthesis of lantadene analogs with marked in vitro inhibition of lung adenocarcinoma and TNF-α induced nuclear factor-kappa B (NF-κB) activation. Bioorg Med Chem Lett, 2014, 24(16): 3814-3818

[23] KameyamaN, ArisawaS, UeyamaJ, et al.. Increase in P-glycoprotein accompanied by activation of protein kinase Cα and NF-κB p65 in the livers of rats with streptozotocin-induced diabetes. Biochim Biophys Acta, 2008, 1782(5): 355-360

[24] OhsakiY, ShirakawaH, MiuraA, et al.. Vitamin K suppresses the lipopolysaccharide-induced expression of inflammatory cytokines in cultured macrophage-like cells via the inhibition of the activation of nuclear factor κB through the repression of IKKα/β phosphorylation. J Nutr Biochem, 2010, 21(11): 1120-1126

[25] ZelarayanL, GehrkeC, BergmannMW. Role of beta-catenin in adult cardiac remodeling. Cell Cycle, 2007, 6(17): 2120-2126

[26] GarciamartínA, ReyesgarciaR, GarcíafontanaB, et al.. Relationship of Dickkopf1 (DKK1) with cardiovascular disease and bone metabolism in Caucasian type 2 diabetes mellitus. PLoS One, 2014, 9(11): e111703

[27] Yung-ChienH, ChangPJ, ChengH, et al.. Protective effects of miR-29a on diabetic glomerular dysfunction by modulation of DKK1/Wnt/β-catenin signaling. Sci Rep, 2016, 6: 30575

[28] SemënovMV, ZhangX, HeX. DKK1 Antagonizes Wnt Signaling without Promotion of LRP6 Internalization and Degradation. J Biol Chem, 2008, 283(31): 21 427-21 432

[29] HuY, GuX, LiR, et al.. Glycogen synthase kinase-3β inhibition induces nuclear factor-κB-mediated apoptosis in pediatric acute lymphocyte leukemia cells. J Exp Clin Cancer Res, 2010, 29(1): 1-8

[30] HoeflichKP, LuoJ, RubieEA, et al.. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature, 2000, 406(6791): 86-90