hydroxysafflor-yellow-a and Ischemia

Myocardial ischemia damages cardiac myocytes in part via opening of the mitochondrial permeability transition pore. Preventing this pore's opening is therefore a useful therapeutic goal in treating cardiovascular disease. Hydroxysafflor yellow A has been proposed as a nontoxic alternative to other agents that modulate mitochondrial permeability transition pore opening. In this study, we proposed that hydroxysafflor yellow A prevents mitochondrial permeability transition pore formation in anoxic cardiac myocytes, and thus protects the cell from damage seen during reoxygenation of the cardiac myocytes. Experiments with hydroxysafflor yellow A transport in aerobic myocytes show that roughly 50% of the extracellular dye concentration crosses the cell membrane in a 2-h incubation. In our anoxia/reoxygenation protocol, hydroxysafflor yellow A modulated both the reduction of viability and the loss of rod-shaped cells that attend anoxia and reoxygenation. Hydroxysafflor yellow A's protective effect was similar to that of cyclosporin A, an agent known to inhibit mitochondrial permeability transition pore opening. In additional experiments, plated myocytes were loaded with calcein/MitoTracker Red, then examined for intracellular dye distribution/morphology after anoxia/reoxygenation. Hydroxysafflor yellow A-containing cells showed a cardioprotective pattern similar to that of cyclosporin A (an agent known to close the mitochondrial permeability transition pore). We conclude that hydroxysafflor yellow A can enter the cardiac myocyte and is able to modulate anoxia/reoxygenation-induced damage by interacting with the mitochondrial permeability transition pore.

Topics: Animals; Cardiotonic Agents; Carthamus; Chalcone; Female; Hypoxia; Ischemia; Male; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocytes, Cardiac; Quinones; Rats; Rats, Sprague-Dawley

The flowers of Carthamus tinctorius L. are widely used in traditional Chinese medicine to treat cerebrovascular and cardiovascular diseases. Hydroxysafflor yellow A (HSYA), the main constituent of C. tinctorius L. flowers, is known for its multiple biological activities. The present study investigated the effects of HSYA on angiogenesis in vitro and in a mouse hindlimb ischemia model.. Using human umbilical vein endothelial cells (HUVEC) in vitro and a mouse hindlimb ischemia model in vivo, the angiogenic role of HSYA was evaluated.. HSYA significantly increased the capillary-like tube formation and migration of HUVEC. HSYA not only induced a rise in the expression of angiopoietin 1 and Tie-2 but it also increased phosphorylation of Tie-2, Akt, and extracellular signal-regulated kinase 1/2. Furthermore, an anti-Tie-2 neutralizing antibody significantly inhibited HSYA-induced HUVEC tube formation and migration. In vivo, the recovery of perfusion of ischemic hindlimb tissue after femoral artery interruption was significantly increased in HSYA-treated mice compared to vehicle controls. Consistent with these results, the arteriole and capillary densities in ischemic gastrocnemius muscles were significantly increased in HSYA-treated mice.. These results indicate the potential utility of HSYA for the treatment of ischemic diseases.

Topics: Angiogenesis Inducing Agents; Angiopoietin-1; Animals; Blood Flow Velocity; Cell Movement; Cells, Cultured; Chalcone; Disease Models, Animal; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Hindlimb; Human Umbilical Vein Endothelial Cells; Humans; Ischemia; Male; Mice, Inbred C57BL; Muscle, Skeletal; Neovascularization, Physiologic; Phosphorylation; Proto-Oncogene Proteins c-akt; Quinones; Receptor, TIE-2; Regional Blood Flow; Signal Transduction; Time Factors