Resveratrol Ameliorates Aortic Calcification in Ovariectomized Rats via SIRT1 Signaling

Abstract

Postmenopausal women are at an increased risk of vascular calcification which is defined as the pathological deposition of minerals in the vasculature, and is strongly linked with increased cardiovascular disease risk. Since estrogen-replacement therapy is associated with increased cancer risk, there is a strong need for safer therapeutic approaches. In this study we aimed to investigate the protective and therapeutic effects of the phytoestrogen resveratrol against vascular calcification in ovariectomized rats, a preclinical model of postmenopause. Furthermore, we aimed to compare the effects of resveratrol to those of estrogen and to explore the mechanisms underpinning those effects. Treatment with resveratrol or estrogen ameliorated aortic calcification in ovariectomized rats, as shown by reduced calcium deposition in the arterial wall. Mechanistically, the effects of resveratrol and estrogen were mediated via the activation of SIRT1 signaling. SIRT1 protein expression was downregulated in the aortas of ovariectomized rats, and upregulated in rats treated with resveratrol or estrogen. Moreover, resveratrol and estrogen reduced the levels of the osteogenic markers: runt-related transcription factor 2 (RUNX2), osteocalcin and alkaline phosphatase (ALP) which have been shown to play a role during vascular calcification. Additionally, the senescence markers (p53, p16 and p21) which were also reported to play a role in the pathogenesis of vascular calcification, were reduced upon treatment with resveratrol and estrogen. In conclusion, the phytoestrogen resveratrol may be a safer alternative to estrogen, as a therapeutic approach against the progression of vascular calcification during postmenopause.

Mammalian Sirtuins and Their Relevance in Vascular Calcification

“…And Wnt/β-catenin is well verified to play an important role in osteogenesis calcification and alveolar bone remodeling ( Wang et al, 2022 ). Similarly, SIRT1 signaling has been found to be activate during the resveratrol-induced improvement of aortic calcification in ovariectomized rats ( Hammad et al, 2021 ).…”

Oxidative Stress in Calcific Aortic Valve Stenosis: Protective Role of Natural Antioxidants

“…It is a scavenger of various free radicals and can improve risk factors for diseases such as cancer, diabetes, osteoporosis, and cardiovascular disease [ 115 , 116 ]. Resveratrol can alleviate arterial calcification in ovariectomized rats (preclinical model of post-menopause) mediated by the sirtuin1 (SIRT1) signaling pathway [ 117 ]. Resveratrol upregulated the expression of SIRT1, downregulated the expression of calcification markers Runx2, osteocalcin, and ALP, increased OPG along with downregulation of RANKL, and decreased the expression of senescence markers, such as p53, p21, and p16 [ 117 ].…”

“…Resveratrol can alleviate arterial calcification in ovariectomized rats (preclinical model of post-menopause) mediated by the sirtuin1 (SIRT1) signaling pathway [ 117 ]. Resveratrol upregulated the expression of SIRT1, downregulated the expression of calcification markers Runx2, osteocalcin, and ALP, increased OPG along with downregulation of RANKL, and decreased the expression of senescence markers, such as p53, p21, and p16 [ 117 ]. Similarly, resveratrol has been reported to effectively inhibit the development of aortic valve calcification and stenosis even in aged mice model (Apoe −/− mice challenged with the Western diet for 16 weeks) [ 81 ].…”

Contribution of Oxidative Stress (OS) in Calcific Aortic Valve Disease (CAVD): From Pathophysiology to Therapeutic Targets

“…The most known polyphenolic representative is likely resveratrol (3,5,4′-trihydroxytrans-stilbene), which is found in berries and grapes [ 81 ]. The major antioxidant effects are mediated by SIRT1, Nrf2, and the ER (estrogen receptor) reducing arterial calcification by downregulating RUNX2, osteocalcin, and ALP [ 83 , 126 , 127 , 128 ]. In addition to having an anti-inflammatory impact, precursors of resveratrol (palmitoylethanolamide, polydatin) significantly reduced the expression of VCAM, ICAM-1, TNF- α, IL-1, alleviating vascular injury [ 19 , 49 , 129 , 130 , 131 , 132 ].…”