Dose‐Dependent, Therapeutic Potential of Angiotensin‐(1–7) for the Treatment of Pulmonary Arterial Hypertension

Abstract

The effects of the heptapeptide angiotensin-(1-7) (Ang-(1-7)), via its receptor Mas, oppose many of the effects of the classic angiotensin II signaling pathway, and pharmacological exploitation of this effect is currently actively pursued for a wide range of cardiovascular, neoplastic, or immunological disorders. On the basis of its vasodilatory and antiproliferative properties, Ang-(1-7) has consequentially also been proposed as a novel therapeutic strategy for the treatment of pulmonary arterial hypertension (PAH). In this study, we tested the effectiveness of Ang-(1-7) and its stable, cyclic analog cAng-(1-7) over a range of doses for their therapeutic potential in experimental PAH. In the monocrotaline (MCT) rat model of PAH, Ang-(1-7) or cAng-(1-7) were injected in doses of 30, 100, 300, or 900 μg kg, and effects on pulmonary hemodynamics and vascular remodeling were assessed. Five weeks after MCT injection, right ventricular systolic pressure (RVSP) was significantly reduced for 3 dose groups treated with Ang-(1-7) (100, 300, and 900 μg kg) and for all dose groups treated with cAng-(1-7), as compared to untreated controls, yet the total reduction of RVSP was <50% at best and thus markedly lower than that with a positive treatment control with ambrisentan. Medial-wall thickness in pulmonary arterioles was only slightly reduced, without reaching significance, for any of the tested Ang-(1-7) compounds and doses. The reported moderate attenuation of PAH does not confirm the previously postulated high promise of this strategy, and the therapeutic usefulness of Ang-(1-7) may be limited in PAH relative to that in other cardiovascular diseases.Keywords: pulmonary hypertension, vascular remodeling, renin-angiotensin system. Pulmonary arterial hypertension (PAH) is a rare but ultimately fatal disease defined by an increase in mean pulmonary arterial pressure to >25 mmHg at rest or >30 mmHg during exercise.1 The pathogenesis of PAH is very diverse, in that PAH may be heritable or idiopathic or develop in association with a number of diseases, such as systemic sclerosis or HIV infection. The pathology of PAH is characterized by endothelial dysfunction, which becomes apparent as an imbalance in the release of vasoconstrictive and vasodilatory factors, such as endothelin and nitric oxide (NO), leading to pulmonary vasoconstriction and ultimately promoting structural remodeling of the pulmonary vasculature, resulting in a persistent elevation in pulmonary vascular resistance. 2,3 A series of therapeutic drugs have been approved for the treatment of PAH that target three different pathways: prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. 4 While these drugs have helped to improve life expectancy and quality of life in PAH patients in the past 2 decades, mortality remains high, as one-third of PAH patients die within 3 years of diagnosis; this emphasizes the need for further research and improved therapeutic options.

Counter-regulatory renin–angiotensin system in cardiovascular disease

“…Furthermore, stud ies in animal models have shown that administration of angiotensin 1-7 included in cyclodextrin complexes has neuroprotective effects and improves muscle dam age induced by eccentric cardiac overload [38][39][40][41][42][43][44] . A stable, cyclic analogue of angiotensin 1-7 moderately reduced right ventricular systolic pressure in a rat model of monocrotaline induced PAH, but no significant changes were observed in the medial wall thickness of pulmo nary arterioles 45 . To optimize the protective potential of this angiotensin 1-7 analogue for the treatment of PAH, the compound can potentially be combined with a neprilysin inhibitor or an ACE2 activator 46 ; whether this approach is effective in maintaining high levels of angiotensin 1-7 requires further investigation.…”

The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

“…modulation elicited by PAH, increasing parasympathetic and decreasing sympathetic cardiac activation (445). Although the administration of ANG-(1-7) and cyclic ANG-(1-7) immediately after induction of PAH in rats demonstrated no superiority of the MAS agonists compared with conventional treatments, the route of administration as well as the high doses used, which may have effects via AT1 receptors, suggest caution in interpreting the authors' conclusions (51). On the other hand, these results are important in designing future evaluations of the therapeutic potential of ANG-(1-7) for PAH treatment.…”

The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases

“…Liu et al overexpressed ACE2 globally via the adenoviral gene delivery, and found no differences in blood pressure between control and ACE2-overexpressing rats [200]. Breitling et al found insignificant therapeutic usefulness of ANG (1–7) in an animal model of experimental pulmonary hypertension [205], whereas Zhang et al reported that activation of Mas during myocardial infarction contributed to, rather than attenuated, ischemia-reperfusion injury in rats [206]. In the latter study, inhibition of Mas G-protein signaling surprisingly improved coronary blood flow, reduced myocardial infarct size, and provided long-term cardioprotection [206].…”