Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension.
BACKGROUND
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.


OBJECTIVE
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.


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.
Ferreira
Anderson J
AJ
Department of Physiology and Functional Genomics, College of Medicine, Gainesville, FL 32610, USA.
Shenoy
Vinayak
V
Yamazato
Yoriko
Y
Sriramula
Srinivas
S
Francis
Joseph
J
Yuan
Lihui
L
Castellano
Ronald K
RK
Ostrov
David A
DA
Oh
Suk Paul
SP
Katovich
Michael J
MJ
Raizada
Mohan K
MK
D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D055104:Infusions, Subcutaneous; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects; D044004:Xanthones / Q000008:administration & dosage / Q000494:pharmacology*
C541435:1-((2-dimethylamino)ethylamino)-4-(hydroxymethyl)-7-((4-methylphenyl)sulfonyloxy)-9H-xanthene-9-one; D044004:Xanthones; D016753:Interleukin-10; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2