Rationale: It has been proposed that an activated renin angiotensin system (RAS) causes an imbalance between the vasoconstrictive and vasodilator mechanisms involving the pulmonary circulation leading to the development of pulmonary hypertension (PH). Recent studies have indicated that angiotensin-converting enzyme 2 (ACE2), a member of the vasoprotective axis of the RAS, plays a regulatory role in lung pathophysiology, including pulmonary fibrosis and acute lung disease. Based on these observations, we propose the hypothesis that activation of endogenous ACE2 can shift the balance from the vasoconstrictive, proliferative axis (ACE-Ang II-AT1R) to the vasoprotective axis [ACE2-Ang-(1–7)-Mas] of the RAS, resulting in the prevention of PH. Objectives: We have taken advantage of a recently discovered synthetic activator of ACE2, XNT (1-[(2-dimethylamino) ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one), to study its effects on monocrotaline-induced PH in rats to support this hypothesis. Methods: The cardiopulmonary effects of XNT were evaluated in monocrotaline-induced PH rat model. Measurements and Main Results: A single subcutaneous treatment of monocrotaline in rats resulted in elevated right ventricular systolic pressure, right ventricular hypertrophy, increased pulmonary vessel wall thickness, and interstitial fibrosis. These changes were associated with increases in the mRNA levels of renin, ACE, angiotensinogen, AT1 receptors, and proinflammatory cytokines. All these features of PH were prevented in these monocrotaline-treated rats by chronic treatment with XNT. In addition, XNT caused an increase in the antiinflammatory cytokine, IL-10. Conclusions: These observations provide conceptual support that activation of ACE2 by a small molecule can be a therapeutically relevant approach for treating and controlling PH.

Recent studies confirm that C-H...O hydrogen bonds have many, if not all, of the spectroscopic and physical earmarks of “traditional” H-bonds. Only more recently have we come to understand that these contacts are operative not only in protein-protein recognition, but enzyme-substrate interactions (with implications for drug design), biological and nonbiological transition state stabilization and have, in some circumstances, a strength and geometric predictability to make them useful in the construction of materials and supramolecular assemblies. Forays into each of these areas have come largely due to advances in computational protocols and spectroscopic instrumentation. This review discusses the most recent findings related to the nature (i.e. strength, geometrical preferences, and spectroscopic features) and function (i.e. in supramolecular design and synthesis, conformational control, enantioselective synthesis, and biology) of C-H...O interactions in a variety of chemical and biological systems. An understanding of the key features of these interactions should promote their deployment in target areas like medicinal chemistry and materials science.