Endothelial dysfunction of coronary resistance vessels in apoE-/- mice involves NO but not prostacyclin-dependent mechanisms.
OBJECTIVE: We have analyzed the extent of endothelial dysfunction in cardiac resistance vessels of hyperlipidaemic apoE-/- mice and explored whether NO and/or prostacyclin dependent pathways are involved. METHODS: Coronary resistance was measured in isolated perfused hearts from WT and apoE-/- mice. To discriminate between NO and PGI(2)-dependent flow responses, we made use of the finding that acetylcholine (ACh) predominantly activates the prostaglandin pathway whereas bradykinin (Bk) mainly acts via NO in murine cardiac resistance vessels. RESULTS: Basal coronary flow as well as the ACh induced vasodilation (0.1-1 microM) were not different between WT and apoE-/- hearts (flow increase+100%). Similarly, vasodilation in response to the prostacyclin mimetic iloprost reached the same levels. In contrast, the Bk-stimulated [3.3 microM Bk] coronary flow was reduced from 31.6+/-4.2 in WT to 19.2+/-2.7 ml min(-1) g(-1) in apoE-/- hearts. NOS inhibition by ethylisothiourea (ETU, 10 microM) reduced basal as well as Bk-stimulated coronary flow in WT and apoE-/- hearts to the same extent. RT-PCR and Western analysis demonstrated that neither eNOS expression nor protein levels were reduced. Similarly, the flow response to the NO donor SNAP (0.3-33 microM) was not altered suggesting that soluble guanylyl cyclase was not affected. Intracoronary application of superoxide dismutase augmented the Bk-induced vasodilation of apoE-/- hearts almost back to WT levels (26.6+/-3.3 ml min(-1) g(-1)). In line with this finding the NADPH induced O(2)(-) formation was enhanced in cardiac extracts from apoE-/- hearts. CONCLUSION: apoE-/- hearts develop a hemodynamically relevant endothelial dysfunction at the level of coronary resistance vessels most likely via inactivation of bioavailable NO by superoxide anions. The function of the prostacyclin system is not altered.[1]References
- Endothelial dysfunction of coronary resistance vessels in apoE-/- mice involves NO but not prostacyclin-dependent mechanisms. Gödecke, A., Ziegler, M., Ding, Z., Schrader, J. Cardiovasc. Res. (2002) [Pubmed]
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