Angiotensin II type II receptor (AT2R) and the Mas receptor (MasR) belong to the ‘protective arm’ of the RAS. Either AT2R or MasR stimulation is known to evoke a number of cardiovascular effects, including acute vasodilatation as well as chronic anti-fibrotic effects. Compound 21 (C21) is the prototypical AT2R agonist, while Ang (1–7) has mainly been used in chronic studies to stimulate MasR, although this heptapeptide is relatively nonselective. Therefore, we examined if selective AT2R (using C21) or MasR (using AVE0991) stimulation would evoke similar anti-fibrotic phenotypes to that of combination treatment, which may implicate similar signalling mechanisms.Design and Method:
To investigate if AT2R and MasR pharmacological co-stimulation would provide additional protection against end-organ damage in stroke-prone spontaneously hypertensive rats (SP-SHR) than either treatment alone. Adult male SP-SHR, aged 20–22 weeks, were treated for 4 weeks with either saline (n = 7), AT2R agonist C21 (0.03 mg/kg/day, n = 6), MasR agonist AVE0991 (24 μg/kg/h, n = 3), or a combination of both (n = 4), subcutaneously via osmotic mini-pump. Blood pressure (tail-cuff) was measured at days 0, 14 and 28 of the protocol. At the end of treatment, indices of aberrant cardiac remodeling (cardiac hypertrophy and interstitial fibrosis) were quantified.Results:
None of the treatments influenced elevated blood pressure or cardiac hypertrophy in SP-SHR. However, cardiac interstitial fibrosis (assessed by picrosirius red staining) was strikingly attenuated from control levels (collagen volume fraction 5.5%) to approximately half those levels by each treatment (2.6%, 2.7% for C21 and AVE0991, respectively, both P < 0.01 versus untreated) while there was no additive anti-fibrotic effect of combination treatment (collagen volume fraction 2.4%).Conclusions:
Pharmacological stimulation of AT2R and/or MasR exhibited marked cardiac anti-fibrotic effects without influencing blood pressure. Ongoing studies will address whether or not similar mechanisms contribute to altered extracellular matrix.