TY - JOUR
T1 - Myocyte specific overexpression of myoglobin impairs angiogenesis after hind-limb ischemia
AU - Hazarika, Surovi
AU - Angelo, Michael
AU - Li, Yongjun
AU - Aldrich, Amy J.
AU - Odronic, Shelley I.
AU - Yan, Zhen
AU - Stamler, Jonathan S.
AU - Annex, Brian H.
PY - 2008/12
Y1 - 2008/12
N2 - Objective - In preclinical models of peripheral arterial disease the angiogenic response is typically robust, though it can be impaired in conditions such as hypercholesterolemia and diabetes where the endothelium is dysfunctional. Myoglobin (Mb) is expressed exclusively in striated muscle cells. We hypothesized that myocyte specific overexpression of myoglobin attenuates ischemia-induced angiogenesis even in the presence of normal endothelium. Methods and Results - Mb overexpressing transgenic (MbTg, n=59) and wild-type (WT, n=56) C57B1/6 mice underwent unilateral femoral artery ligation/excision. Perfusion recovery was monitored using Laser Doppler. Ischemia-induced changes in muscle were assessed by protein and immunohistochemistry assays. Nitrite/nitrate and protein-bound NO, and vasoreactivity was measured. Vasoreactivity was similar between MbTg and WT. In ischemic muscle, at d14 postligation, MbTg increased VEGF-A, and activated eNOS the same as WT mice but nitrate/nitrite were reduced whereas protein-bound NO was higher. MbTg had attenuated perfusion recovery at d21 (0.37 ± 0.03 versus 0.47 ± 0.02, P<0.05), d28 (0.40±0.03 versus 0.50±0.04, P<0.05), greater limb necrosis (65.2% versus 15%, P<0.001), a lower capillary density, and greater apoptosis versus WT. Conclusion - Increased Mb expression in myocytes attenuates angiogenesis after hind-limb ischemia by binding NO and reducing its bioavailability. Myoglobin can modulate the angiogenic response to ischemia even in the setting of normal endothelium.
AB - Objective - In preclinical models of peripheral arterial disease the angiogenic response is typically robust, though it can be impaired in conditions such as hypercholesterolemia and diabetes where the endothelium is dysfunctional. Myoglobin (Mb) is expressed exclusively in striated muscle cells. We hypothesized that myocyte specific overexpression of myoglobin attenuates ischemia-induced angiogenesis even in the presence of normal endothelium. Methods and Results - Mb overexpressing transgenic (MbTg, n=59) and wild-type (WT, n=56) C57B1/6 mice underwent unilateral femoral artery ligation/excision. Perfusion recovery was monitored using Laser Doppler. Ischemia-induced changes in muscle were assessed by protein and immunohistochemistry assays. Nitrite/nitrate and protein-bound NO, and vasoreactivity was measured. Vasoreactivity was similar between MbTg and WT. In ischemic muscle, at d14 postligation, MbTg increased VEGF-A, and activated eNOS the same as WT mice but nitrate/nitrite were reduced whereas protein-bound NO was higher. MbTg had attenuated perfusion recovery at d21 (0.37 ± 0.03 versus 0.47 ± 0.02, P<0.05), d28 (0.40±0.03 versus 0.50±0.04, P<0.05), greater limb necrosis (65.2% versus 15%, P<0.001), a lower capillary density, and greater apoptosis versus WT. Conclusion - Increased Mb expression in myocytes attenuates angiogenesis after hind-limb ischemia by binding NO and reducing its bioavailability. Myoglobin can modulate the angiogenic response to ischemia even in the setting of normal endothelium.
KW - Angiogenesis
KW - Animal models of human disease
KW - Endothelium/vascular type/nitric oxide
KW - Genetically altered mice
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U2 - 10.1161/ATVBAHA.108.170951
DO - 10.1161/ATVBAHA.108.170951
M3 - Article
C2 - 18818418
AN - SCOPUS:57549109453
SN - 1079-5642
VL - 28
SP - 2144
EP - 2150
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 12
ER -