Antiatherosclerotic therapy using cell differentiation-promoting effect of biologically active peptides

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We first examined the expression of receptors for natriuretic peptides(ANP, BNP, CNP) in wire-injured femoral arteries in mice. Significant expressions of both GC-A(receptor for ANP and BNP) and GC-B(receptor for CNP) were found in neointima after 3 weeks of wire injury, and the expression level of GC-A was higher than that of GC-B. When the extent of wire injury-induced neointima formation was compared between wild-type and GC-A knockout mice, the area of neointima was greater in GC-A knockout mice. This result suggested the possibility that endogenous ANP and BNP released from the heart inhibited atherosclerotic change of femoral artery after wire injury. To further examine the role of endogenous ANP and BNP in neovascularization observed in atherosclerotic lesions, lower limb-ischemic model was made in both wild-type and GC-A knockout mice, and the recovery of blood flow was evaluated. The blood flow was restored to about 70% after 3 weeks in wild-type mice. On the other hand, inter … More estingly, the recovery rate of blood flow in GC-A knockout mice was about 20%, and approximately half of them had necrotized lower limbs. The finding suggested that endogenous ANP and BNP might play an important role in the angiogenesis in ischemic lesions. From these results, an in vitro study was designed to investigate whether ANP and BNP, stimulate cyclic GMP(cGMP) accumulation in vascular endothelial progenitor cells derived from human blood mononuclear cells. As a result, intracellular cGMP levels were remarkably elevated after stimulation with ANP and BNP, suggesting that these peptides have a direct effect on endothelial progenitor cells. Our findings indicate that endogenous ANP and BNP are involved not only in the inhibition of the formation of atherosclerotic lesions, but also in the promotion of neovascularization in those lesions. Thus, the present study provided a great progress forclinical application of antiatherosclerotic therapy using cell differentiation-promoting effect of ANP and BNP. We will forward further investigations about antiatherosclerotic effects and therapeutic application of CNP, adrenomedulin, and ghrelin. Less