Featured Article: Induction of heme oxygenase with hemin improves pericardial adipocyte morphology and function in obese Zucker rats by enhancing proteins of regeneration
Restricted accessResearch articleFirst published online January, 2015
Featured Article: Induction of heme oxygenase with hemin improves pericardial adipocyte morphology and function in obese Zucker rats by enhancing proteins of regeneration
Oxidative stress and inflammation are implicated in tissue remodeling, hypertrophy, and organ malfunction. Since heme-oxygenase (HO) is a cytoprotective enzyme with effects against oxidative stress and inflammation, we investigated the effects of upregulating HO with hemin on adipocyte hypertrophy, proteins of repair/regeneration including beta-catenin, Oct3/4 and Pax2 as well as pro-fibrotic/remodeling proteins like osteopontin and transforming growth factor-beta (TGF-β) in pericardial adipose tissue from obese Zucker rats (ZRs). Treatment with hemin significantly reduced pericardial adipose tissue inflammation/oxidative stress, suppressed osteopontin and TGF-β, and attenuated pericardial adipocyte hypertrophy in obese ZRs. These were associated with enhanced expression of the stem/progenitor-cell marker cKit; the potentiation of several proteins of regeneration including beta-catenin, Oct3/4, Pax2; and improved pericardial adipocyte morphology. Interestingly, the amelioration of adipocyte hypertrophy in hemin-treated animals was accompanied by improved adipocyte function, evidenced by increased levels of pericardial adipose tissue adiponectin. Furthermore, hemin significantly reduced hypertriglyceridemia and hypercholesteromia in obese ZRs. The protective effects of hemin were accompanied by robust potentiation HO activity and the total antioxidant capacity, whereas the co-administration of hemin with the HO inhibitor, stannous mesoporphyrin abolished the effects of hemin. These data suggest that hemin improves pericardial adipocyte morphology and function by enhancing proteins of repair and regeneration, while concomitantly abating inflammatory/oxidative insults and suppressing extracellular-matrix/profibrotic and remodeling proteins. The reduction of hypertriglyceridemia, hypercholesteromia, pericardial adiposity, and pericardial adipocyte hypertrophy with corresponding improvement of adipocyte morphology/function in hemin-treated animals suggests that HO inducers may be explored for the design of novel remedies against cardiac complications arising from excessive adiposity.
NdisangJFJadhavA. Hemin therapy suppresses inflammation and retroperitoneal adipocyte hypertrophy to improve glucose metabolism in obese rats co-morbid with insulin-resistant type-2 diabetes. Diabetes Obes Metab2013; 15: 1029–39.
3.
YangJEliassonBSmithUCushmanSWShermanAS. The size of large adipose cells is a predictor of insulin resistance in first-degree relatives of type 2 diabetic patients. Obesity (Silver Spring)2012; 20: 932–8.
4.
HotamisligilGSShargillNSSpiegelmanBM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science1993; 259: 87–91.
5.
HamdyOPorramatikulSAl-OzairiE. Metabolic obesity: the paradox between visceral and subcutaneous fat. Curr Diabetes Rev2006; 2: 367–73.
6.
HotamisligilGS. Inflammation and metabolic disorders. Nature2006; 444: 860–7.
7.
RositoGAMassaroJMHoffmannURubergFLMahabadiAAVasanRSO’DonnellCJFoxCS. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample: the Framingham Heart Study. Circulation2008; 117: 605–13.
8.
LiuJFoxCSHicksonDAMayWLDingJCarrJJTaylorHA. Pericardial fat and echocardiographic measures of cardiac abnormalities: The Jackson Heart Study. Diabetes Care2011; 34: 341–6.
NdisangJFLaneNJadhavA. The heme oxygenase system abates hyperglycemia in Zucker diabetic fatty rats by potentiating insulin-sensitizing pathways. Endocrinology2009; 150: 2098–108.
11.
MosenHSalehiAAlmPHenningssonRJimenez-FeltstromJOstensonCGEfendicSLundquistI. Defective glucose-stimulated insulin release in the diabetic Goto-Kakizaki (GK) rat coincides with reduced activity of the islet carbon monoxide signaling pathway. Endocrinology2005; 146: 1553–8.
12.
MosenHSalehiAHenningssonRLundquistI. Nitric oxide inhibits, and carbon monoxide activates, islet acid alpha-glucoside hydrolase activities in parallel with glucose-stimulated insulin secretion. J Endocrinol2006; 190: 681–93.
13.
NdisangJFJadhavA. Heme oxygenase system enhances insulin sensitivity and glucose metabolism in streptozotocin-induced diabetes. Am J Physiol Endocrinol Metab2009; 296: E829–41.
14.
NdisangJFLaneNJadhavA. Upregulation of the heme oxygenase system ameliorates postprandial and fasting hyperglycemia in type 2 diabetes. Am J Physiol Endocrinol Metab2009; 296: E1029–41.
15.
NdisangJFJadhavA. Upregulating the heme oxygenase system suppresses left ventricular hypertrophy in adult spontaneously hypertensive rats for 3 months. J Card Fail2009; 15: 616–28.
16.
NdisangJFWangR. Age-related alterations in soluble guanylyl cyclase and cGMP pathway in spontaneously hypertensive rats. J Hypertens2003; 21: 1117–24.
17.
NdisangJFWangR. Alterations in heme oxygenase/carbon monoxide system in pulmonary arteries in hypertension. Exp Biol Med (Maywood)2003; 228: 557–63.
18.
NdisangJFTabienHEWangR. Carbon monoxide and hypertension. J Hypertens2004; 22: 1057–74.
19.
AbrahamNGKappasA. Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev2008; 60: 79–127.
20.
NdisangJF. Role of heme oxygenase in inflammation, insulin-signalling, diabetes and obesity. Mediators Inflamm2010; 2010: 359732–359732.
21.
NdisangJFLaneNSyedNJadhavA. Up-regulating the heme oxygenase system with hemin improves insulin sensitivity and glucose metabolism in adult spontaneously hypertensive rats. Endocrinology2010; 151: 549–60.
22.
ParkSYKimKHSeoKWBaeJUKimYHLeeSJLeeWSKimCD. Resistin derived from diabetic perivascular adipose tissue upregulates vascular expression of osteopontin via AP-1 signaling pathway. J Pathol2014; 232: 87–97.
23.
PandaDKunduGCLeeBIPeriAFohlDChackalaparampilIMukherjeeBBLiXDMukherjeeDCSeidesSRosenbergJStarkKMukherjeeAB. Potential roles of osteopontin and alphaVbeta3 integrin in the development of coronary artery restenosis after angioplasty. Proc Natl Acad Sci USA1997; 94: 9308–13.
24.
LiJJZhuCGYuBLiuYXYuMY. The role of inflammation in coronary artery calcification. Ageing Res Rev2007; 6: 263–70.
25.
ChapmanJMilesPDOfrecioJMNeelsJGYuJGResnikJLWilkesJTalukdarSThaparDJohnsonKSearsDD. Osteopontin is required for the early onset of high fat diet-induced insulin resistance in mice. PLoS One2010; 5: e13959–e13959.
26.
SinghMFosterCRDalalSSinghK. Role of osteopontin in heart failure associated with aging. Heart Fail Rev2010; 15: 487–94.
27.
RallDP. Problems remain to be resolved in the area of quantitative risk assessment. Regul Toxicol Pharmacol1992; 15: 104–5.
28.
MatsuiYJiaNOkamotoHKonSOnozukaHAkinoMLiuLMorimotoJRittlingSRDenhardtDKitabatakeAUedeT. Role of osteopontin in cardiac fibrosis and remodeling in angiotensin II-induced cardiac hypertrophy. Hypertension2004; 43: 1195–201.
29.
ZeydaMGollingerKTodoricJKieferFWKeckMAszmannOPragerGZlabingerGJPetzelbauerPStulnigTM. Osteopontin is an activator of human adipose tissue macrophages and directly affects adipocyte function. Endocrinology2011; 152: 2219–27.
30.
DahiyaSGivvimaniSBhatnagarSQipshidzeNTyagiSCKumarA. Osteopontin-stimulated expression of matrix metalloproteinase-9 causes cardiomyopathy in the mdx model of Duchenne muscular dystrophy. J Immunol2011; 187: 2723–31.
HeneidiSSimermanAAKellerESinghPLiXDumesicDAChazenbalkG. Awakened by cellular stress: Isolation and characterization of a novel population of pluripotent stem cells derived from human adipose tissue. PLoS One2013; 8: e64752–e64752.
33.
VillanuevaSCarrenoJESalazarLVergaraCStrodthoffRFajreFCéspedesCSáezPJIrarrázabalCBartolucciJFigueroaFVioCP. Human mesenchymal stem cells derived from adipose tissue reduce functional and tissue damage in a rat model of chronic renal failure. Clin Sci (Lond)2013; 125: 199–210.
34.
SodhiKPuriNKimDHHindsTDStechschulteLAFaveroGRodellaLShapiroJIJudeDAbrahamNG. PPARdelta binding to heme oxygenase 1 promoter prevents angiotensin II-induced adipocyte dysfunction in Goldblatt hypertensive rats. Int J Obes (Lond)2014; 38: 456–65.
35.
JadhavATiwariSLeePNdisangJF. The heme oxygenase system selectively enhances the anti-inflammatory macrophage-m2 phenotype, reduces pericardial adiposity, and ameliorated cardiac injury in diabetic cardiomyopathy in zucker diabetic Fatty rats. J Pharmacol Exp Ther2013; 345: 239–49.
36.
Ndisang JF, Jadhav A. Hemin therapy suppresses inflammation and retroperitoneal adipocyte hypertrophy to improve glucose metabolism in obese rats co-morbid with insulin resistant type-2 diabetes. Diabetes Obes Metab 2013;15:1029–39.
37.
SalleyTNMishraMTiwariSJadhavANdisangJF. The heme oxygenase system rescues hepatic deterioration in the condition of obesity co-morbid with type-2 diabetes. PLoS One2013; 8: e79270–e79270.
38.
JadhavATorlakovicENdisangJF. Interaction among heme oxygenase, nuclear factor-{kappa}B, and transcription activating factors in cardiac hypertrophy in hypertension. Hypertension2008; 52: 910–7.
39.
JadhavATorlakovicENdisangJF. Hemin therapy attenuates kidney injury in deoxycorticosterone acetate-salt hypertensive rats. Am J Physiol Renal Physiol2009; 296: F521–F34.
40.
NdisangJFMishraM. The heme oxygenase system selectively suppresses the proinflammatory macrophage m1 phenotype and potentiates insulin signaling in spontaneously hypertensive rats. Am J Hypertens2013; 26: 1123–31.
41.
NdisangJFJadhavAMishraM. The heme oxygenase system suppresses perirenal visceral adiposity, abates renal inflammation and ameliorates diabetic nephropathy in zucker diabetic fatty rats. PLoS One2014; 9: e87936–e87936.
42.
JadhavANdisangJF. Treatment with heme arginate alleviates adipose tissue inflammation and improves insulin sensitivity and glucose metabolism in a rat model of human primary aldosteronism. Free Radic Biol Med2012; 53: 2277–86.
43.
ReavenGM. Insulin resistance, the insulin resistance syndrome, and cardiovascular disease. Panminerva Med2005; 47: 201–10.
44.
RubinsteinJPelosiAVedreAKotaruPAbelaGS. Hypercholesterolemia and myocardial function evaluated via tissue doppler imaging. Cardiovasc Ultrasound2009; 7: 56–56.
45.
YunokiKNakamuraKMiyoshiTEnkoKKuboMMurakamiMHataYKohnoKMoritaHKusanoKFItoH. Impact of hypertriglyceridemia on endothelial dysfunction during statin +/- ezetimibe therapy in patients with coronary heart disease. Am J Cardiol2011; 108: 333–9.
46.
AsselinCDucharmeANtimbaneTRuizMFortierAGuertinMCLavoieJDiazALevyETardifJCDes RosiersC. Circulating levels of linoleic acid and HDL-cholesterol are major determinants of 4-hydroxynonenal protein adducts in patients with heart failure. Redox Biol2014; 2: 148–55.
47.
YanoMYamamotoTNishimuraNGotohTWatanabeKIkedaKGaranYTaguchiRNodeKOkazakiTOikeY. Increased oxidative stress impairs adipose tissue function in sphingomyelin synthase 1 null mice. PLoS One2013; 8: e61380–e61380.
48.
CrujeirasABDiaz-LagaresACarreiraMCAmilMCasanuevaFF. Oxidative stress associated to dysfunctional adipose tissue: a potential link between obesity, type 2 diabetes mellitus and breast cancer. Free Radic Res2013; 47: 243–56.
49.
DelantyNReillyMPPraticoDLawsonJAMcCarthyJFWoodAEOhnishiSTFitzgeraldDJFitzGeraldGA. 8-epi PGF2 alpha generation during coronary reperfusion. A potential quantitative marker of oxidant stress in vivo. Circulation1997; 95: 2492–9.
50.
JuliusUDrelVRGrasslerJObrosovaIG. Nitrosylated proteins in monocytes as a new marker of oxidative-nitrosative stress in diabetic subjects with macroangiopathy. Exp Clin Endocrinol Diabetes2009; 117: 72–77.
51.
Lagoda G, Sezen SF, Hurt KJ, Cabrini MR, Mohanty DK, Burnett AL. Sustained nitric oxide (NO)-releasing compound reverses dysregulated NO signal transduction in priapism. FASEB J 2014;28:76–84.
52.
DarwishRSAmiridzeNAarabiB. Nitrotyrosine as an oxidative stress marker: Evidence for involvement in neurologic outcome in human traumatic brain injury. J Trauma2007; 63: 439–42.
53.
LagodaGSezenSFHurtKJCabriniMRMohantyDKBurnettAL. Sustained nitric oxide (NO)-releasing compound reverses dysregulated NO signal transduction in priapism. FASEB J2014; 28: 76–84.
54.
Moreno-NavarreteJMEscoteXOrtegaFSerinoMCampbellMMichalskiMCLavilleMXifraGLucheEDomingoPSabaterMPardoGWagetASalvadorJGiraltMRodriguez-HermosaJICampsMKolditzCIViguerieNGalitzkyJDecaunesPRicartWFrühbeckGVillarroyaFMingroneGLanginDZorzanoAVidalHVendrellJBurcelinRVidal-PuigAFernández-RealJM. A role for adipocyte-derived lipopolysaccharide-binding protein in inflammation- and obesity-associated adipose tissue dysfunction. Diabetologia2013; 56: 2524–37.
55.
AkiKShimizuAMasudaYKuwaharaNAraiTIshikawaAFujitaEMiiANatoriYFukunagaYFukudaY. ANG II receptor blockade enhances anti-inflammatory macrophages in anti-glomerular basement membrane glomerulonephritis. Am J Physiol Renal Physiol2010; 298: F870–82.
56.
HirataYTabataMKurobeHMotokiTAkaikeMNishioCHigashidaMMikasaHNakayaYTakanashiSIgarashiTKitagawaTSataM. Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue. J Am Coll Cardiol2011; 58: 248–55.
57.
ZhangXWangZLiJGuDLiSShenCSongZ. Increased 4-hydroxynonenal formation contributes to obesity-related lipolytic activation in adipocytes. PLoS One2013; 8: e70663–e70663.
58.
BurgessAPVanellaLBellnerLGotlingerKFalckJRAbrahamNGSchwartzmanMLKappasA. Heme oxygenase (HO-1) rescue of adipocyte dysfunction in HO-2 deficient mice via recruitment of epoxyeicosatrienoic acids (EETs) and adiponectin. Cell Physiol Biochem2012; 29: 99–110.
59.
LinJFernandezIRoyK. Development of feeder-free culture systems for generation of ckit+sca1+ progenitors from mouse iPS cells. Stem Cell Rev2011; 7: 736–47.
60.
ParkJKKiMRLeeEMKimAYYouSYHanSYLeeEJHongIHKwonSHKimSJRandoTAJeongKS. Losartan improves adipose tissue-derived stem cell niche by inhibiting transforming growth factor-beta and fibrosis in skeletal muscle injury. Cell Transplant2012; 21: 2407–24.
61.
HuangHTangQZWangABChenMYanLLiuCJiangHYangQBianZYBaiXZhuLHWangLLiH. Tumor suppressor A20 protects against cardiac hypertrophy and fibrosis by blocking transforming growth factor-beta-activated kinase 1-dependent signaling. Hypertension2010; 56: 232–9.
FujisakaSUsuiIIkutaniMAminuddinATakikawaATsuneyamaKMahmoodAGodaNNagaiYTakatsuKTobeK. Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1alpha-dependent and HIF-1alpha-independent manner in obese mice. Diabetologia2013; 56: 1403–12.
64.
TiwariSMishraMJadhavAGergerCLeePWeberLNdisangJF. The risk of heart failure and cardiometabolic complications in obesity may be masked by an apparent healthy status of normal blood glucose. Oxid Med Cell Longev2013; 2013: 253657–253657.
65.
WeisNWeigertAvon KnethenABruneB. Heme oxygenase-1 contributes to an alternative macrophage activation profile induced by apoptotic cell supernatants. Mol Biol Cell2009; 20: 1280–8.
