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Effects of D-4F on vasodilation, oxidative stress, angiostatin, myocardial inflammation and angiogenic potential in Tight-skin

Posted Sep 11 2009 4:56pm

By Dorothee Weihrauch and Colleague

Systemic sclerosis ( scleroderma, SSc ) is an autoimmune, connective tissue disorder that is characterized by impaired vascular function, increased oxidative stress, inflammation of internal -/+ organs, and impaired angiogenesis. Tight skin mice (Tsk ) have a defect in fibrillin-1, resulting in replication of many of the myocardial and vascular features seen in humans with SSc.

D-4F is an apolipoprotein A-I (apoA-I) mimetic that improves vascular function in diverse diseases such -/+ as hypercholesterolemia, influenza, and sickle cell disease. Tsk mice were treated with either phosphate buffered saline (PBS) or D-4F (1 mg/kg/d for 6-8 weeks). Acetylcholine and flow-induced vasodilation were examined in facialis arteries. Proinflammatory HDL (p-HDL) in murine and human plasma samples was determined by the cell-free assay. Angiostatin levels in murine and human plasma samples were determined by western blot analysis.

Hearts were examined for changes in angiostatin and autoantibodies against oxidized phosphotidyl choline (ox-PC). Angiogenic potential in thin sections of murine hearts was assessed by an in vitro VEGF-induced endothelial cell (EC) tube formation assay. D-4F improved endothelium-, eNOS--/+ -/+ dependent and flow-mediated vasodilation in Tsk mice.

Tsk mice had higher plasma proinflammatory HDL and angiostatin levels than C57BL/6 mice, as did SSc patients compared -/+ mice also had higher triglycerides than C57BL/6 mice. D-4F to healthy control subjects. Tsk -/+ -/+ reduced p-HDL, angiostatin and triglycerides in the plasma of Tsk mice. Tsk hearts contained notably higher levels of angiostatin and autoantibodies against ox-PC than control -/+ hearts. D-4F ablated angiostatin in Tsk hearts and reduced autoantibodies against ox-PC by -/+ -/+ mice. Angiogenic potential in Tsk hearts was >50% compared to hearts from untreated Tsk -/+ increased only when the Tsk mice were treated with D-4F (1 mg/kg/d, 6-8 weeks) and cultured -/+ sections of hearts from the D-4F-treated Tsk mice were incubated with D-4F (10 ?g/mL, 5-7 -/+
days).

Failure to treat the thin sections of hearts and Tsk mice with D-4F esulted in loss of VEGF-induced EC tube formation. D-4F improves vascular function, decreases myocardial -/+ inflammation, and restores angiogenic potential in the hearts of Tsk mice. As SSc patients have -/+ increased plasma p-HDL and angiostatin levels similar to the Tsk mice, D-4F may be effective at treating vascular complications in patients with SSc.

Key Words: systemic sclerosis, angiostatin, angiogenesis, D-4F, tight skin mice

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