The coronary angiogenetic effect of heparin: experimental basis and clinical evidence.
Heparin is a highly sulfated polysaccharide consisting of a repeating disaccharide structure as found in other glycosaminoglycanes. The intravenous and subcutaneous formulation of the drug is routinely used for its well-known, time-honored antithrombotic effect. However, available evidences linking heparin to angiogenesis raise the possibility of a therapeutically relevant antiischemic effect of the drug. Molecular biology data show that in a hypoxic milieu heparin could facilitate angiogenesis through interactions with a family of polypeptide growth factor mitogens that stimulate endothelial cell proliferation. Experimental data suggest that heparin can augment collateral circulation when combined with other potentially angiogenetic factors, such as repeated ischemia, coronary occlusion, or physical exercise. Clinical data, although very initial, encompassing a total of only 41 heparin-treated patients with coronary artery disease, suggest that heparin facilitates collateral development stimulated by exercise-induced myocardial ischemia in humans. According to the heparin-collateral hypothesis, the mechanism of action of heparin as an antiischemic medication would be independent of its anticoagulant action. The molecular targets of heparin are Factor Xa and IIa for antithrombotic action, heparin-binding growth factors (including fibroblast growth factor and vascular endothelial growth factor) for angiogenesis. The antithrombotic effect is not linked to a cellular target, whereas the angiogenetic effect directly stimulates endothelial cells. The molecular cofactor required for effect is antithrombin III for antithrombosis, and possibly endogenous adenosine for angiogenesis. The therapeutic effect is achieved within minutes or hours for antithrombosis, and within weeks or months for angiogenesis.
Bombardini
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IRCCS Rizzoli, Bologna, CNR Institute of Clinical Physiology, Pisa, Italy.
Picano
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E
D000787:Angina Pectoris / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D003097:Collateral Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects
D006493:Heparin