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Reversal of diabetic stem‐cell mobilopathy by angiotensin‐(1‐7) via rho‐kinase downregulation (1051.5)
Author(s) -
Vasam Goutham,
Raizada Mohan,
Jarajapu Yagna
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1051.5
Subject(s) - endocrinology , medicine , progenitor cell , rho associated protein kinase , angiotensin ii , ex vivo , downregulation and upregulation , stem cell , diabetes mellitus , stromal cell , saline , renin–angiotensin system , kinase , in vivo , chemistry , biology , microbiology and biotechnology , blood pressure , biochemistry , gene
Mobilization of bone marrow stem/progenitor cells (BMSPCs) that maintain cardiovascular health is impaired in diabetes. We have previously shown that Angiotensin (Ang)‐(1‐7) increases the vasoreparative potential of dysfunctional BMSPCs from individuals with diabetes. In this study we tested the effect of Ang‐(1‐7) on the impaired mobilization of BMSPCs in diabetes. Furthermore, the role of Rho‐kinase in the beneficial effects of Ang‐(1‐7) was evaluated. Lean control or obese db/db (type 2 diabetic) (DB) mice were treated with continuous infusion of saline or Ang‐(1‐7) (1 µg/Kg/min) for four weeks by using subcutaneous osmotic pumps. Subsets of peripheral blood lineage‐negative cells, Lin‐Sca‐1+, Lin‐cKit+ and Lin‐Sca‐1+cKit+ cells, were enumerated after four weeks of treatment. All subsets of BMSPCs were lower in DB (compared to control, P<0.05), and were increased by Ang‐(1‐7) treatment to control levels. The number and proliferation of BM‐resident SPCs, and the migration to stromal‐derived factor‐1α (SDF, 100 nM) ex vivo were reduced in DB compared to control group (P<0.01) and this dysfunction was reversed to normal by Ang‐(1‐7) treatment. Expression of Rho‐kinase isoforms, ROCK‐1 and ROCK‐2, were higher in DB‐BMSPCs (compared to control, P<0.01) that was down‐regulated by Ang‐(1‐7) to normal levels. Furthermore, ex vivo treatment of BMSPCs from DB with a non‐specific ROCK inhibitor, Y27632 (10 μM), restored their migration to SDF. These results suggest that Ang‐(1‐7) increases BMSPC‐mobilization in diabetes, in part, via down‐regulation of ROCK. Together with our previous observations, Ang‐(1‐7) appears to be a promising target for the treatment of diabetic stem‐cell mobilopathy and for enhancing the outcomes of cell‐based therapies in individuals with diabetes. Grant Funding Source : Supported by American Heart Association‐13SDG16960025