Potentiating Bradykinin Pathway by Genetic Suppression of Endothelin-converting Enzyme-1 Prevented Hypoxic induced Pulmonary Hypertension and Right Ventricular Hypertrophy

Yoko Suzuki1, Sunu Budhi Raharjo2, Nakayama Kazuhiko1, Nicolas Vignon1, Susi Heiden1, Nur Arfian1, Anggoro Budi Hart Opo1, Keiko Yagi1, Noriaki Emoto1,2. 1Kobepharmaceutical University, Clinical Pharmacy,658-8558, Japan, 2Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Japan.

Endothelin-converting enzyme-1 (ECE-1) is a metallopeptidase with broad substrate specificity. This enzyme not only produced vasoconstrictor endothelin-1 (ET-1), but also inactivated vasodilator bradykinin in vitro. This study investigated the effect of ECE-1 deficiency on the pulmonary vascular response to hypoxia in mice. ECE-1 heterozygous mice (n = 16) developed less hypoxic pulmonary hypertension and vascular remodeling than paired controls (n = 16). After 3 weeks of hypoxia, ECE-1+/− mice had lower RV systolic pressure, RV/(LV+S) and % pulmonary artery wall thickness than the WT mice. Although the levels of ET-1 peptide in serum and lung increased ∼3-4 folds in both groups after 3 weeks of hypoxic exposure, the ET-1 level was not different between the two genotypes under both normoxic and hypoxic conditions. Surprisingly, we found that at the normoxic state the levels of bradykinin peptide was ∼3-folds higher in lungs of ECE-1+/- than WT mice (P<0.001). Chronic hypoxia dramatically reduced the lungs bradykinin in WT mice to almost undetectable levels but only slightly did so in KO mice. These results suggest a novel pathophysiological role of ECE-1 in the pathogenesis of hypoxic pulmonary hypertension. The beneficial effects of ECE-1 deficiency in this model can be attributed to the preservation and potentiation of bradykinin action and not to reduced ET-1 production. ECE-1 inhibiton should provide another plausible therapeutic strategy towards pulmonary hypertension.