The protective effects of alamandine on angiotensin II-induced cardiac dysfunction and remodeling in rats

Alamandine (Ala), a relatively recent addition to the renin-angiotensin system (RAS), is a heptapeptide sharing structural similarities with angiotensin-(1-7). This peptide has garnered significant attention due to its distinctive antihypertensive, vasodilatory, and antifibrotic effects. In this study, we sought to determine whether Ala acts as a counter-regulatory agent against angiotensin II-induced cardiac hypertrophy, fibrosis, and inflammation in rats. Male SD rats (n=6 in each group) received a two-week subcutaneous infusion of vehicle (saline), angiotensin II (ANG II, 150 ng/kg/min), or a combination of ANG II and Ala (50 ng/kg/min) via mini osmotic pumps. Left ventricular (LV) function was evaluated through echocardiography. Histological analysis of cardiac hypertrophy and fibrosis was conducted using Hematoxylin Eosin and Trichome-Mason staining, respectively. Compared to the vehicle group, treatment with Ala significantly (*p<0.05) attenuated ANG II-induced cardiac mass (659.27 ± 54.26* vs. 824.48 ± 40.38 mg) with reduced LV thickness and end-diastolic volume. Ala treatment also improved cardiac function, as indicated by reduced global longitudinal strain and myocardial performance index. Histological images revealed that Ala treatment markedly reduced cardiomyocyte area (383.63* ± 7.20 vs 490.59 ± 13.13 μm²) and fibrosis area (5.22* ± 0.93 vs. 9.64 ± 0.36%) in rats treated with ANG II, along with reduced mRNA expression of pro-hypertrophic markers such as brain natriuretic peptide (4.29 ± 0.50* vs 7.53 ± 0.68, fold change) and β-myosin heavy chain (6.11 ± 0.61* vs 10.29 ± 1.02), as well as pro-fibrosis markers collagen 1 (5.72 ± 0.59* vs 10.56 ± 1.69), fibronectin (2.18 ± 0.34* vs 4.69 ± 0.70), and α-smooth muscle actin (2.14 ± 0.42* vs 3.85 ± 0.06), when compared to the rats treated with ANG II alone. Flow cytometry analysis also showed that Ala treatment significantly reduced ANG II-induced immune responses in the heart by reducing immune cell populations including CD4, CD8 T cells, B cells and NK cells, and increasing presence of anti-inflammatory M2 monocytes. Additionally, the mRNA levels of interlukin-6, CD 68, and chemokine monocyte chemoattractant protein-1 were significantly decreased in Ala-treated rats. Furthermore, treatment with Ala reversed ANG II-induced alterations in the mRNA expression of angiotensin-converting enzyme (ACE, 2.05 ± 0.16* vs. 3.08 ± 0.25), angiotensin type 1 receptor (1.45 ± 0.22* vs. 2.56 ± 0.31), and ACE 2 (1.08 ± 0.10** vs. 0.38 ± 0.06) in the LV of the heart. Taken together, these findings demonstrate that alamandine exerts a protective effect against ANG II-induced cardiac dysfunction, hypertrophy, fibrosis, and inflammation, potentially acting as a protective component of the RAS to counteract the adverse effects of ANG II. Alamandine might be a potential therapeutic agent in the treatment of cardiovascular disorders. Supported by NIH grants R01 HL139521 & 155091. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.