angiotensin-i and Familial-Primary-Pulmonary-Hypertension

Angiotensin-converting enzyme 2 (ACE2), an ACE homolog, hydrolyzes angiotensin II and opposes its actions, and plays a protective role in the pathogenesis of pulmonary arterial hypertension (PAH). However, the underlying mechanisms involved in the effect of ACE2 on PAH are still uncertain. In this study, we observed the effects of ACE2 activation on endothelial dysfunction and vascular remodeling in the development of severe PAH in rats.. Severe PAH was induced by monocrotaline injection 1 week following left pneumonectomy, and ACE2 was activated by continuous injection of resorcinolnaphthalein. The PAH-related hemodynamics, pathological changes, and endothelium-dependent vasorelaxation were examined to assess the effects of ACE2 activation. In addition, the changes of the main components of the renin-angiotensin system were identified by ELISA or Western blotting.. Severe PAH was established at 3 weeks and was characterized by high pulmonary arterial pressure (45 mmHg), significant right ventricular hypertrophy, neointimal occlusive lesions, and impaired endothelium-dependent relaxation in pulmonary arteries. Coadministration of resorcinolnaphthalein reduced pulmonary arterial pressure, right ventricular hypertrophy, and neointimal formation and shifted the endothelial-dependent responses toward values measured in normal rats. Theses changes were associated with an increase in ACE2 and angiotensin-(1-7) levels and a decrease in ACE and angiotensin II levels, in addition to a decrease in the ACE/ACE2 ratio and the angiotensin II/angiotensin-(1-7) ratio. The beneficial effects of resorcinolnaphthalein were abolished by A-779.. These findings suggested that ACE2 activation by resorcinolnaphthalein improved endothelial function and suppressed neointimal formation in the prevention of severe PAH by the mechanism of mediating the levels of the components of the renin-angiotensin system.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Arterial Pressure; Cytoprotection; Disease Models, Animal; Endothelium, Vascular; Enzyme Activation; Enzyme Activators; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Naphthalenes; Neointima; Peptide Fragments; Peptidyl-Dipeptidase A; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Resorcinols; Severity of Illness Index; Time Factors; Vasodilation

To investigate whether Angiotensin-(1-7) [Ang-(1-7)] could prevent the development of monocrotaline (MCT) induced pulmonary arterial hypertension and vascular remodeling.. 30 Sprgue-Dawely rats were randomly assigned into three groups: control group, pulmonary arterial hypertension (PAH) group and PAH +Ang-(1-7) group. Rats in PAH group and PAH +Ang-(1-7) group received 60 mg/kg monocrotaline (MCT) injection subcutaneously and after 24 hours received either saline or 24 microg/kg/h of Ang-(1-7) injection via osmotic minipumps for 4 weeks. Those rats in control group were firstly injected saline subcutaneously and then received saline injection via osmotic minipumps.. After four weeks, in PAH group, right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), percentage of wall thickness (WT%) and percentage of wall area (WA%) were significantly increased, and the level of endothelial nitric oxide synthase (eNOS) protein, eNOS ser 1177-phosphorylati, Akt-phosphorylation were significantly decreased compared with control group. However, RVSP, RVHI, WT%, WA% were dramatically decreased in PAH+Ang-(1-7) group and the level of eNOS protein, eNOS ser 1177-phosphorylation, Akt-phosphorylation were significantly increased compared with PAH group.. Those results suggest that Ang-(1-7) could prevent the development of monocrotaline induced pulmonary arterial hypertension and vascular remodeling, which appears to be associated with up-regulation of eNOS activation via Akt pathway.

Topics: Angiotensin I; Animals; Familial Primary Pulmonary Hypertension; Hemodynamics; Hypertension, Pulmonary; Male; Monocrotaline; Nitric Oxide Synthase Type III; Peptide Fragments; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley