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Development of a molecular therapy for Peripheral Artery Disease

We first developed an effective gene therapy to overexpress eNOS in mouse models of arterial occlusive disease. We were able to transition to an oral molecular therapy consisting of L-arginine, the substrate for eNOS, tetrahydrobiopterin, an essential co-factor that keeps eNOS in its functional dimeric structure and L-Ascorbate, which restores the shuttle pathway of BH3 to BH4. UMass Med was recently granted a patent for this therapy. Despite the critical importance of nitric oxide bioavailability to innumerable signaling pathways, there is no currently available therapy to increase NO bioavailability. We are about to start a Phase 1 clinical trial to determine the safety and efficacy of our molecular therapy.

Tetrahydrobiopterin, L-arginine and vitamin C act synergistically to decrease oxidant stress and increase nitric oxide that increases blood flow recovery after hindlimb ischemia in the rat.  Yan J, Tie G, Messina LM.  Mol Med. 2012 Oct 24;18:1221-30. doi:  10.2119/molmed.2011.00103.revised. PMID: 23212846

Oral tetrahydrobiopterin improves the beneficial effect of adenoviral-mediated eNOS gene transfer after induction of hindlimb ischemia.  Yan J, Tie G, Hoffman A, Yang Y, Nowicki PT, Messina LM.  Mol Ther. 2010 Aug;18(8):1482-9. doi: 10.1038/mt.2010.109. Epub 2010 Jun 15. PMID: 20551918

Endothelial nitric oxide synthase affects both early and late collateral arterial adaptation and blood flow recovery after induction of hind limb ischemia in mice.  Park B, Hoffman A, Yang Y, Yan J, Tie G, Bagshahi H, Nowicki PT, Messina LM.  J Vasc Surg. 2010 Jan;51(1):165-73. doi: 10.1016/j.jvs.2009.08.045. Epub 2009 Oct 30. PMID: 19879098

Recovery from hind limb ischemia is less effective in type 2 than in type 1 diabetic mice: roles of endothelial nitric oxide synthase and endothelial progenitor cells.  Yan J, Tie G, Park B, Yan Y, Nowicki PT, Messina LM.  J Vasc Surg. 2009 Dec;50(6):1412-22. doi: 10.1016/j.jvs.2009.08.007. Epub 2009 Oct 17. PMID: 19837544

Elucidating the genetic basis of peripheral arterial disease: identification of a quantitative trait locus that determines the phenotypic response to experimental hindlimb ischemia.  Messina LM.  Circulation. 2008 Mar 4;117(9):1127-9. doi: 10.1161/CIRCULATIONAHA.107.752055. No abstract available. PMID: 18316497

Optimization of adenovirus-mediated endothelial nitric oxide synthase delivery in rat hindlimb ischemia.  Yan J, Tang GL, Wang R, Messina LM.  Gene Ther. 2005 Nov;12(22):1640-50. PMID: 16107865


Roles of hematopoietic and mesenchymal stem cells during collateral artery enlargement and the mechanisms by which cardiovascular risk factors impair their function

During collateral artery enlargement, we showed that mesenchymal stem cells play the dual roles of providing a paracrine effect to promote enlargement and transdifferentiating into new endothelial cells.  In a mouse model of Type 2 Diabetes mellitus (T2DM), we showed that T2DM causes Nox 4-induced oxidant stress in MSCs that reduces their capacity to promote neovascularization after the induction of limb ischemia as well as to transdifferentiate into endothelial cells (EC). Thus, rather than transdifferentiating into ECs, MSCs transdifferentiated into adipocytes.  We restored the capacity of MSCs from T2DM mice to promote postischemic neovascularization by using siRNA to downregulate Nox 4 and thereby unraveled a potential human MSC therapy for Peripheral Artery Disease.

Mesenchymal stem cells as a treatment for peripheral arterial disease: current status and potential impact of type II diabetes on their therapeutic efficacy.  Yan J, Tie G, Xu TY, Cecchini K, Messina LM.  Stem Cell Rev. 2013 Jun;9(3):360-72. doi: 10.1007/s12015-013-9433-8. Review. PMID: 23475434

Type 2 diabetes restricts multipotency of mesenchymal stem cells and impairs their capacity to augment postischemic neovascularization in db/db mice.  Yan J, Tie G, Wang S, Messina KE, DiDato S, Guo S, Messina LM.  J Am Heart Assoc. 2012 Dec;1(6):e002238. doi: 10.1161/JAHA.112.002238. Epub 2012 Dec 19. PMID: 23316315


Role of regulation of inflammation and immunity at the level of HSCs

We have identified the epigenetic mechanism through which hypercholesterolemia increases the incidence of colorectal cancer by inducing an ox-LDL-dependent increase in hematopoietic stem cell oxidant stress that reduces the number and cytotoxicity of NKT and γδT cells, thereby impairing cancer immunosurveillance. In a parallel manner, we have shown that type 2 diabetes causes impaired wound healing by inducing a Nox2-dependent increase in hematopoietic stem cell oxidant stress that reduces the number of wound macrophages and skews them towards inflammatory rather than angiogenic macrophages. Taken together, we believe we have uncovered a heretofore unrecognized critical role of regulation of inflammation and immunity at the level of HSCs.

Type 2 diabetes impairs the ability of skeletal muscle pericytes to augment postischemic neovascularization in db/db mice.  Hayes KL, Messina LM, Schwartz LM, Yan J, Burnside AS, Witkowski S. Am J Physiol Cell Physiol. 2018 May 1;314(5):C534-C544. doi: 10.1152/ajpcell.00158.2017. Epub 2018 Jan 10. PMID: 29351404

Diabetes impairs wound healing by Dnmt1-dependent dysregulation of hematopoietic stem cells differentiation towards macrophages. Yan J, Tie G, Wang S, Tutto A, DeMarco N, Khair L, Fazzio TG, Messina LM. Nat Commun. 2018 Jan 2;9(1):33. doi: 10.1038/s41467-017-02425-z. PMID: 29295997

Hypercholesterolemia Increases Colorectal Cancer Incidence by Reducing Production of NKT and γδ T Cells from Hematopoietic Stem Cells. Tie G, Yan J, Khair L, Messina JA, Deng A, Kang J, Fazzio T, Messina LM. Cancer Res. 2017 May 1;77(9):2351-2362. doi: 10.1158/0008-5472.CAN-16-1916. Epub 2017 Mar 1. PMID: 28249902

Hypercholesterolemia induces oxidant stress that accelerates the ageing of hematopoietic stem cells.
Tie G, Messina KE, Yan J, Messina JA, Messina LM.  J Am Heart Assoc. 2014 Jan 27;3(1):e000241. doi: 10.1161/JAHA.113.000241. PMID: 24470519

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