Overexpression of angiopoietin-1 increases CD133+/c-kit+ cells and reduces myocardial apoptosis in db/db mouse infarcted hearts
Heng Zeng, Lanfang Li, Jian-Xiong Chen, Heng Zeng, Lanfang Li, Jian-Xiong Chen
Abstract
Hematopoietic progenitor CD133(+)/c-kit(+) cells have been shown to be involved in myocardial healing following myocardial infarction (MI). Previously we demonstrated that angiopoietin-1(Ang-1) is beneficial in the repair of diabetic infarcted hearts. We now investigate whether Ang-1 affects CD133(+)/c-kit(+) cell recruitment to the infarcted myocardium thereby mediating cardiac repair in type II (db/db) diabetic mice. db/db mice were administered either adenovirus Ang-1 (Ad-Ang-1) or Ad-β-gal systemically immediately after ligation of the left anterior descending coronary artery (LAD). Overexpression of Ang-1 resulted in a significant increase in CXCR-4/SDF-1α expression and promoted CD133(+)/c-kit(+), CD133(+)/CXCR-4(+) and CD133(+)/SDF-1α(+) cell recruitment into ischemic hearts. Overexpression of Ang-1 led to significant increases in number of CD31(+) and smooth muscle-like cells and VEGF expression in bone marrow (BM). This was accompanied by significant decreases in cardiac apoptosis and fibrosis and an increase in myocardial capillary density. Ang-1 also upregulated Jagged-1, Notch3 and apelin expression followed by increases in arteriole formation in the infarcted myocardium. Furthermore, overexpression of Ang-1 resulted in a significant improvement of cardiac functional recovery after 14 days of ischemia. Our data strongly suggest that Ang-1 attenuates cardiac apoptosis and promotes cardiac repair by a mechanism involving in promoting CD133(+)/c-kit(+) cells and angiogenesis in diabetic db/db mouse infarcted hearts.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
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References
- Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell. 1996;87:1171–1180.
- Papapetropoulos A, Fulton D, Mahboubi K, Kalb RG, O’Connor DS, et al. Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J Biol Chem. 2000;275:9102–9105.
- Joussen AM, Poulaki V, Tsujikawa A, Qin W, Qaum T, et al. Suppression of diabetic retinopathy with angiopoietin-1. Am J Pathol. 2002;160:1683–1693.
- Chen JX, Stinnett A. Ang-1 gene therapy inhibits hypoxia-inducible factor-1alpha (HIF-1alpha)-prolyl-4-hydroxylase-2, stabilizes HIF-1alpha expression, and normalizes immature vasculature in db/db mice. Diabetes. 2008;57:3335–3343.
- Isner JM, Asahara T. Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J Clin Invest. 1999;103:1231–1236.
- Schachinger V, Assmus B, Britten MB, Honold J, Lehmann R, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol. 2004;44:1690–1699.
- Britten MB, Abolmaali ND, Assmus B, Lehmann R, Honold J, et al. Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation. 2003;108:2212–2218.
- Hu CH, Li ZM, Du ZM, Zhang AX, Rana JS, et al. Expanded human cord blood-derived endothelial progenitor cells salvage infarcted myocardium in rats with acute myocardial infarction. Clin Exp Pharmacol Physiol. 2010;37:551–556.
- Glass CE, Singal PK, Singla DK. Heart Fail Rev 15: 581–588. 10.1007/s10741-010-9172-8 [doi]; 2010. Stem cells in the diabetic infarcted heart.
- Thum T, Fraccarollo D, Schultheiss M, Froese S, Galuppo P, et al. Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes. 2007;56:666–674.
- Yoon YS, Uchida S, Masuo O, Cejna M, Park JS, et al. Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy: restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. Circulation. 2005;111:2073–2085.
- Tuo QH, Zeng H, Stinnett A, Yu H, Aschner JL, et al. Critical role of angiopoietins/Tie-2 in hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis. Am J Physiol Heart Circ Physiol. 2008;294:H2547–H2557.
- Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, et al. Cell 118: 149–161. 10.1016/j.cell.2004.07.004 [doi]; S0092867404006622 [pii]; 2004. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche.
- Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, et al. Lancet 362: 697–703. S0140-6736(03)14232-8 [pii];10.1016/S0140-6736(03)14232-8 [doi]; 2003. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy.
- Chen JX, Zeng H, Tuo QH, Yu H, Meyrick B, et al. NADPH oxidase modulates myocardial Akt, ERK1/2 activation and angiogenesis after hypoxia/reoxygenation. Am J Physiol Heart Circ Physiol. 2007;292:H1664–H1674.
- Chen JX, Stinnett A. Disruption of Ang-1/Tie-2 signaling contributes to the impaired myocardial vascular maturation and angiogenesis in type II diabetic mice. Arterioscler Thromb Vasc Biol. 2008;28:1606–1613.
- Kim H, Cho HJ, Kim SW, Liu B, Choi YJ, et al. Circ Res 107: 602–614. CIRCRESAHA.110.218396 [pii];10.1161/CIRCRESAHA.110.218396 [doi]; 2010. CD31+ cells represent highly angiogenic and vasculogenic cells in bone marrow: novel role of nonendothelial CD31+ cells in neovascularization and their therapeutic effects on ischemic vascular disease.
- Dallabrida SM, Ismail NS, Pravda EA, Parodi EM, Dickie R, et al. FASEB J 22: 3010–3023. fj.07-100966 [pii];10.1096/fj.07-100966 [doi]; 2008. Integrin binding angiopoietin-1 monomers reduce cardiac hypertrophy.
- Takahashi K, Ito Y, Morikawa M, Kobune M, Huang J, et al. Mol Ther 8: 584–592. S1525001603002302 [pii]; 2003. Adenoviral-delivered angiopoietin-1 reduces the infarction and attenuates the progression of cardiac dysfunction in the rat model of acute myocardial infarction.
- Voo S, Dunaeva M, Eggermann J, Stadler N, Waltenberger J. J Intern Med 265: 238–249. JIM2011 [pii];10.1111/j.1365-2796.2008.02011.x [doi]; 2009. Diabetes mellitus impairs CD133+ progenitor cell function after myocardial infarction.
- Barcelos LS, Duplaa C, Krankel N, Graiani G, Invernici G, et al. Circ Res 104: 1095–1102. CIRCRESAHA.108.192138 [pii];10.1161/CIRCRESAHA.108.192138 [doi]; 2009. Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling.
- Invernici G, Madeddu P, Emanueli C, Parati EA, Alessandri G. Cytotechnology 58: 43–47. 10.1007/s10616-008-9167-7 [doi]; 2008. Human fetal aorta-derived vascular progenitor cells: identification and potential application in ischemic diseases.
- Hu X, Dai S, Wu WJ, Tan W, Zhu X, et al. Circulation 116: 654–663. CIRCULATIONAHA.106.672451 [pii];10.1161/CIRCULATIONAHA.106.672451 [doi]; 2007. Stromal cell derived factor-1 alpha confers protection against myocardial ischemia/reperfusion injury: role of the cardiac stromal cell derived factor-1 alpha CXCR4 axis.
- Frederick JR, Fitzpatrick JR, III, McCormick RC, Harris DA, Kim AY, et al. Circulation 122: S107–S117. 122/11_suppl_1/S107 [pii];10.1161/CIRCULATIONAHA.109.930404 [doi]; 2010. Stromal cell-derived factor-1alpha activation of tissue-engineered endothelial progenitor cell matrix enhances ventricular function after myocardial infarction by inducing neovasculogenesis.
- Chen JX, Lawrence ML, Cunningham G, Christman BW, Meyrick B. HSP90 and Akt modulate Ang-1-induced angiogenesis via NO in coronary artery endothelium. J Appl Physiol. 2004;96:612–620.
- Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med. 2000;6:460–463.
- Suchting S, Freitas C, le NF, Benedito R, Breant C, et al. Negative regulators of vessel patterning. Novartis Found Symp. 2007;283:77–80.
- High FA, Jain R, Stoller JZ, Antonucci NB, Lu MM, et al. Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development. J Clin Invest. 2009;119:1986–1996.
- Dichgans M. Genetics of ischaemic stroke. Lancet Neurol. 2007;6:149–161.
- Joutel A, Monet-Lepretre M, Gosele C, Baron-Menguy C, Hammes A, et al. Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease. J Clin Invest. 2010;120:433–445.
- rboleda-Velasquez JF, Zhou Z, Shin HK, Louvi A, Kim HH, et al. Linking Notch signaling to ischemic stroke. Proc Natl Acad Sci U S A. 2008;105:4856–4861.
- Morrow D, Cullen JP, Cahill PA, Redmond EM. Cyclic strain regulates the Notch/CBF-1 signaling pathway in endothelial cells: role in angiogenic activity. Arterioscler Thromb Vasc Biol. 2007;27:1289–1296.
- Morrow D, Cullen JP, Cahill PA, Redmond EM. Ethanol stimulates endothelial cell angiogenic activity via a Notch- and angiopoietin-1-dependent pathway. Cardiovasc Res. 2008;79:313–321.
- O’Dowd BF, Heiber M, Chan A, Heng HH, Tsui LC, et al. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene. 1993;136:355–360.
- Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun. 1998;251:471–476.
- Zeng XJ, Zhang LK, Wang HX, Lu LQ, Ma LQ, et al. Apelin protects heart against ischemia/reperfusion injury in rat. Peptides. 2009;30:1144–1152.
- Kunduzova O, Alet N, esque-Touchard N, Millet L, Castan-Laurell I, et al. Apelin/APJ signaling system: a potential link between adipose tissue and endothelial angiogenic processes. FASEB J. 2008;22:4146–4153.
- Eyries M, Siegfried G, Ciumas M, Montagne K, Agrapart M, et al. Hypoxia-induced apelin expression regulates endothelial cell proliferation and regenerative angiogenesis. Circ Res. 2008;103:432–440.
- Quazi R, Palaniswamy C, Frishman WH. The emerging role of apelin in cardiovascular disease and health. Cardiol Rev. 2009;17:283–286.
- Kidoya H, Ueno M, Yamada Y, Mochizuki N, Nakata M, et al. Spatial and temporal role of the apelin/APJ system in the caliber size regulation of blood vessels during angiogenesis. EMBO J. 2008;27:522–534.
- Nahrendorf M, Pittet MJ, Swirski FK. Circulation 121: 2437–2445. 121/22/2437 [pii];10.1161/CIRCULATIONAHA.109.916346 [doi]; 2010. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction.
- Kim SW, Kim H, Yoon YS. Regen Med 6: 335-349. 10.2217/rme.11.24 [doi]; 2011. Advances in bone marrow-derived cell therapy: CD31-expressing cells as next generation cardiovascular cell therapy.
- Kim SW, Kim H, Cho HJ, Lee JU, Levit R, et al. J Am Coll Cardiol 56: 593–607. S0735-1097(10)02101-7 [pii];10.1016/j.jacc.2010.01.070 [doi]; 2010. Human peripheral blood-derived CD31+ cells have robust angiogenic and vasculogenic properties and are effective for treating ischemic vascular disease.
- Zubair AC, Malik S, Paulsen A, Ishikawa M, McCoy C, et al. Evaluation of mobilized peripheral blood CD34(+) cells from patients with severe coronary artery disease as a source of endothelial progenitor cells. Cytotherapy. 2010;12:178–189.
- Doi H, Iso T, Shiba Y, Sato H, Yamazaki M, et al. Notch signaling regulates the differentiation of bone marrow-derived cells into smooth muscle-like cells during arterial lesion formation. Biochem Biophys Res Commun. 2009;381:654–659.
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