title: Hyperhomocysteinemia attenuates angiogenesis through reduction of HIF-1α and PGC-1α levels in muscle fibers during hindlimb ischemia.
abstract: Hyperhomocysteinemia (HHcy) is associated with elderly frailty, skeletal muscle injury and malfunction, reduced vascular integrity and function, and mortality. Although HHcy has been implicated in the impairment of angiogenesis after hindlimb ischemia in murine models, the underlying mechanisms are still unclear. We hypothesized that HHcy compromises skeletal muscle perfusion, collateral formation, and arteriogenesis by diminishing postischemic vasculogenic responses in muscle fibers. To test this hypothesis, we created femoral artery ligation in wild-type and heterozygous cystathionine β-synthase (CBS(+/-)) mice (a model for HHcy) and assessed tissue perfusion, collateral vessel formation, and skeletal muscle function using laser-Doppler perfusion imaging, barium angiography, and fatigue tests. In addition, we assessed postischemic levels of VEGF and levels of its muscle-specific regulators: hypoxia-inducible factor (HIF)-1α and peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α. The observations indicated dysregulation of VEGF, HIF-1α, and PGC-1α levels in ischemic skeletal muscles of CBS(+/-) mice. Concomitant with the reduced ischemic angiogenic responses, we also observed diminished leptin expression and attenuated Akt signaling in ischemic muscle fibers of CBS(+/-) mice. Moreover, there was enhanced atrogene, ubiquitin ligases that conjugate proteins for degradation during muscle atrophy, transcription, and reduced muscle function after ischemia in CBS(+/-) mice. These results suggest that HHcy adversely affects muscle-specific ischemic responses and contributes to muscle frailty.
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Veeranki
authors.forename: Srikanth
authors.initials: S
authors.lastname: Givvimani
authors.forename: Sathnur
authors.initials: S
authors.lastname: Pushpakumar
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003541:Cystathionine beta-Synthase / Q000172:deficiency / Q000235:genetics; D005263:Femoral Artery / Q000601:surgery; D015870:Gene Expression; D006614:Hindlimb / Q000098:blood supply*; D020138:Hyperhomocysteinemia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007511:Ischemia / Q000503:physiopathology*; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000098:blood supply / Q000737:chemistry; D018919:Neovascularization, Physiologic / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics; D013550:Swimming; D014157:Transcription Factors / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009124:Muscle Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D042461:Vascular Endothelial Growth Factor A; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D003541:Cystathionine beta-Synthase
keywords: Akt; CD31; angiogenesis; atrogin-1; hyperhomocysteinemia; hypoxia-inducible factor; ischemia; leptin; muscle ring finger-1; peroxisome proliferator-activated receptor-γ coactivator-1α; skeletal muscle; vascular endothelial growth factor