Alamandine improves cardiac remodeling induced by transverse aortic constriction in mice.

Alamandine is the newest identified peptide of the renin-angiotensin system (RAS) and has protective effects in the cardiovascular system. Although the involvement of classical RAS components in the genesis and progression of cardiac remodeling is well known, less is known about the effects of alamandine. Therefore, in the present study we investigated the effects of alamandine on cardiac remodeling induced by transverse aortic constriction (TAC) in mice. Male mice (C57BL/6), 10-12 wk of age, were divided into three groups: sham operated, TAC, and TAC + ALA (30 µg/kg/day alamandine for 14 days). The TAC surgery was performed under ketamine and xylazine anesthesia. At the end of treatment, the animals were submitted to echocardiographic examination and subsequently euthanized for tissue collection. TAC induced myocyte hypertrophy, collagen deposition, and the expression of matrix metalloproteinase (MMP)-2 and transforming growth factor (TGF)-ß in the left ventricle. These markers of cardiac remodeling were reduced by oral treatment with alamandine. Western blotting analysis showed that alamandine prevents the increase in ERK1/2 phosphorylation and reverts the decrease in 5'-adenosine monophosphate-activated protein kinase (AMPK)α phosphorylation induced by TAC. Although both TAC and TAC + ALA increased SERCA2 expression, the phosphorylation of phospholamban in the Thr17 residue was increased solely in the alamandine-treated group. The echocardiographic data showed that there are no functional or morphological alterations after 2 wk of TAC. Alamandine treatment prevents myocyte hypertrophy and cardiac fibrosis induced by TAC. Our results reinforce the cardioprotective role of alamandine and highlight its therapeutic potential for treating heart diseases related to pressure overload conditions.NEW & NOTEWORTHY Alamandine is the newest identified component of the renin-angiotensin system protective arm. Considering the beneficial effects already described so far, alamandine is a promising target for cardiovascular disease treatment. We demonstrated for the first time that alamandine improves many aspects of cardiac remodeling induced by pressure overload, including cell hypertrophy, fibrosis, and oxidative stress markers.

Alamandine attenuates arterial remodelling induced by transverse aortic constriction in mice.

Aims: The renin-angiotensin system (RAS) plays an important role in the pathophysiology of vascular diseases, especially as a mediator of inflammation and tissue remodelling. Alamandine (Ala1-angiotensin-(1-7)) is a new biologically active peptide from the RAS, interacting with Mas-related G-protein-coupled receptor member D. Although a growing number of studies reveal the cardioprotective effects of alamandine, there is a paucity of data on its participation in vascular remodelling associated events. In the present study, we investigated the effects of alamandine on ascending aorta remodelling after transverse aortic constriction (TAC) in mice. Methods and results: C57BL/6J male mice were divided into the following groups: Sham (sham-operated), TAC (operated) and TAC+ALA (operated and treated with alamandine-HPßCD (2-Hydroxypropyl-ß-cyclodextrin), 30 µg/kg/day, by gavage). Oral administration of alamandine for 14 days attenuated arterial remodelling by decreasing ascending aorta media layer thickness and the cells density in the adventitia induced by TAC. Alamandine administration attenuated ascending aorta fibrosis induced by TAC, through a reduction in the following parameters; total collagen deposition, expression collagen III and transforming growth factor-ß (TGF-ß) transcripts, matrix metalloproteinases (MMPs) activity and vascular expression of MMP-2. Importantly, alamandine decreased vascular expression of proinflammatory genes as CCL2, tumour necrosis factor α (TNF-α) and interleukin-1ß (IL-1ß), and was able to increase expression of MRC1 and FIZZ1, pro-resolution markers, after TAC surgery. Conclusion: Alamandine treatment attenuates vascular remodelling after TAC, at least in part, through anti-fibrotic and anti-inflammatory effects. Hence, this work opens new avenues for the use of this heptapeptide also as a therapeutic target for vascular disease.