Bone Marrow Mesenchymal Stem Cells Induce Angiogenesis and Attenuate the Remodeling of Diabetic Cardiomyopathy

Abstract

Independent of the severity of coronary artery disease, diabetic patients have an increased risk of developing heart failure. Diabetic cardiomyopathy (DCM) is characterized by microvascular pathologies and interstitial fibrosis. Mesenchymal stem cells (MSCs) are pluripotent and are able to differentiate into cardiomyocytes and vascular endothelial cells. Studies have demonstrated MSCs transplantation can prevent apoptosis of ischemic heart via upregulation of Akt and eNOS and inhibit myocardial fibrosis of dilated cardiomyopathy by decreasing the expression of matrix metalloproteinase (MMP) in rat models. In order to find out whether transplantation of MSCs is a promising treatment in DCM, we used streptozotocin (STZ) -induced diabetic rats as the model. Exogenous MSCs were injected into the femoral vein 8 weeks after STZ injection. Using independent experimental approaches, we showed that MSCs presented in the myocardium 4 weeks after transplantation and some of them were positive for the cardiac markers Troponin T and myosin heavy chain. MSCs transplantation significantly increased myocardial arteriolar density and decreased the collagen volume in diabetic myocardium resulting in improved cardiac function. Furthermore, MSCs transplantation increased MMP-2 activity and decreased transcriptional level of MMP-9. These results show that MSCs transplantation improved cardiac function in the rat DCM model, possibly through angiogenesis and attenuation of cardiac remodeling.

Diabetic cardiomyopathy - bone marrow mesenchymal stem cell - remodeling - matrix metalloproteinase - tissue inhibitor of matrix metalloproteinase

References

• 1 Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A, Miller L, Guetta E, Zipori D, Kedes LH, Kloner RA, Leor J. Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium:feasibility, cell migration, and body distribution.  Circulation. 2003;  108 863-868
• 2 Bollano E, Omerovic E, Svensson H, Waagstein F, Fu M. Cardiac remodeling rather than disturbed myocardial energy metabolism is associated with cardiac dysfunction in diabetic rats.  Int J Cardiol. 2006;  , Jun 10; [Epub ahead of print]
• 3 Camp TM, Tyagi SC, Senior RM, Hayden MR, Tyagi SC. Gelatinase B (MMP-9) an apoptotic factor in diabetic transgenic mice.  Diabetologia. 2003;  46 1438-1445
• 4 Colucci WS. Molecular and cellular mechanisms of myocardial failure.  Am J Cardiol. 1997;  80 15L-25L
• 5 Creemers EEJM, Cleutjens JPM, Smits JFM, Daemen MJAP. Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure?.  Circ Res. 2001;  89 201-210
• 6 Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS, Dzau VJ. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells.  Nat Med. 2005;  11 367-368
• 7 Hayashi T, Nozawa M, Sohmiya K, Toko H, Nakao M, Okabe M, Terasaki F, Kitaura Y, Kawamura K. Efficacy of pancreatic transplantation on cardiovascular alterations in diabetic rats: an ultrastructural and immunohistochemical study.  Transplant P. 1998;  30 335-338
• 8 Hayashi T, Sohmiya K, Ukimura A, Endoh S, Mori T, Shimomura H, Okabe M, Terasaki F, Kitaura Y. Angiotensin II receptor blockade prevents microangiopathy and preserves diastolic function in the diabetic rat heart.  Heart. 2003;  89 1236-1242
• 9 Ikonomidis JS, Hendrick JW, Parkhurst AM, Herron AR, Escobar PG, Dowdy KB, Stroud RE, Hapke E, Zile MR, Spinale FG. Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: effects of exogenous MMP inhibition.  Am J Physiol Heart Circ Physiol. 2005;  288 H149-H158
• 10 Jesmin S, Sakuma I, Hattori Y, Kitabatake A. Role of angiotensin II in altered expression of molecules responsible for coronary matrix remodeling in insulin-resistant diabetic rats.  Arterioscler Thromb Vasc Biol. 2003;  23 2021-2026
• 11 Korosoglou G, Humpert PM. Non-invasive diagnostic imaging techniques as a window into the diabetic heart: a review of experimental and clinical data.  Exp Clin Endocrinol Diabetes. 2007;  115 211-220
• 12 Min JY, Chen Y, Malek S, Meissner A, Xiang M, Ke Q, Feng X, Nakayama M, Kaplan E, Morgan JP. Cell therapy in the aging hearts of Fisher 344 rats: synergistic effects on myogenesis and angiogenesis.  J Thorac Cardiov Sur. 2005;  130 547-553
• 13 Nagaya N, Kangawa K, Itoh T, Iwase T, Murakami S, Miyahara Y, Fujii T, Uematsu M, Ohgushi H, Yamagishi M, Tokudome T, Mori H, Miyatake K, Kitamura S. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy.  Circulation. 2005;  112 1128-1135
• 14 Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineag e potential of adult human mesenchymal stem cells.  Science. 1999;  284 143-147
• 15 Price J, Verma S, Li Rk. Diabetic dysfunction: is cell transplantation a potential therapy?.  Heart Failure Reviews. 2003;  8 213-219
• 16 Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis.  Circ Res. 2006;  98 596-605
• 17 Roten L, Nemoto S, Simsic J, Coker ML, Rao V, Baicu S, Defreyte G, Soloway PJ, Zile MR, Spinale FG. Effects of gene deletion of the tissue inhibitor of the matrix metalloproteinase-type 1 (TIMP-1) on left ventricular geometry and function in mice.  J Mol Cell Cardiol. 2000;  32 109-120
• 18 Xie Zl, Singh M, Singh K. Differential regulation of matrix metalloproteinase-2 and -9 expression and activity in adult rat cardiac fibroblasts in response to interleukin-1.  J Biol Chem. 2004;  279 39513-39519
• 19 Uemura R, Xu M, Ahmad N, Ashraf M. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling.  Circ Res. 2006;  98 1414-1421
• 20 Xu M, Wani M, Dai YS, Wang J, Yan M, Ayub A, Ashraf M. Differentiation of bone marrow stromal cells into the cardiac phenotype requires intercellular communication with myocytes.  Circulation. 2004;  110 2658-2665
• 21 Yoon YS, Uchida S, Masuo O, Cejna M, Park JS, Gwon HC, Kirchmair R, Bahlman F, Walter D, Curry C, Hanley A, Isner JM, Losordo DW. 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

1 Nan Zhang and Jiahui Li contributed equally to this work.

Correspondence