Hesperetin, a Promising Dietary Supplement for Preventing the Development of Calcific Aortic Valve Disease

Abstract

Background: No effective therapeutic agents for calcific aortic valve disease (CAVD) are available currently. Dietary therapy has been proposed as a novel treatment strategy for various diseases. As a flavanone, hesperetin is widely abundant in citrus fruits and has been proven to play a protective role against multiple diseases. However, the role of hesperetin in CAVD remains unclear. Methods: Human aortic valve interstitial cells (VICs) were isolated from aortic valve leaflets. A mouse model of aortic valve stenosis was constructed through direct wire injury (DWI). Immunoblotting, immunofluorescence staining, and flow cytometry were used to investigate the roles of sirtuin 7 (Sirt7) and nuclear factor erythroid 2-related factor 2 (Nrf2) in hesperetin-mediated protective effects in VICs. Results: Hesperetin supplementation protected the mice from wire-injury-induced aortic valve stenosis; in vitro, hesperetin suppressed the lipopolysaccharide (LPS)-induced activation of NF-κB inflammatory cytokine secretion and osteogenic factors expression, reduced ROS production and apoptosis, and abrogated LPS-mediated injury to the mitochondrial membrane potential and the decline in the antioxidant levels in VICs. These benefits of hesperetin may have been obtained by activating Nrf2–ARE signaling, which corrected the dysfunctional mitochondria. Furthermore, we found that hesperetin could directly bind to Sirt7 and that the silencing of Sirt7 decreased the effects of hesperetin in VICs and potently abolished the ability of hesperetin to increase Nrf2 transcriptional activation. Conclusions: Our work demonstrates that hesperetin plays protective roles in the aortic valve through the Sirt7–Nrf2–ARE axis; thus, hesperetin might be a potential dietary supplement that could prevent the development of CAVD.

Sirtuins as Players in the Signal Transduction of Citrus Flavonoids

“…hampering the release of pro-inflammatory cytokines and ROS production, mitigati dysfunctional mitochondria, via the upregulation of Nrf2 [200].…”

“…In this regard, it has been reported that HSP was able to target SIRT7, exerting a protective effect against calcific aortic valve disease both in vitro and in vivo. This effect was due to HSP's capability to directly bind SIRT7, hampering the release of pro-inflammatory cytokines and ROS production, mitigating dysfunctional mitochondria, via the upregulation of Nrf2 [200].…”

“…Citrus Flavonoid Effect Reference C57BL/6 mice/ Docking studies/Human VICs HSP Protective effect in the aortic valve, increasing the SIRT7-mediated activation of the Nrf2-ARE axis [200] PC12 cells FA Neuroprotective effect through the upregulation of SIRT1 and SIRT7 [201] Hesperetin (HSP), ferulic acid (FA).…”

Antioxidant, Antiapoptotic, and Anti-Inflammatory Effects of Hesperetin in a Mouse Model of Lipopolysaccharide-Induced Acute Kidney Injury

“…Hesperetin is a flavonoid mainly found in citrus fruits and has been known to possess antioxidant and anti-inflammatory activities [ 13 , 14 ]. Accumulating evidence suggests that this compound exerts beneficial effects on a variety of inflammatory diseases, including obstructive kidney disease and diabetic nephropathy [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. In this study, hesperetin alleviated structural and functional renal injury in LPS-injected mice, as evidenced by the amelioration of histological tubular damage, attenuation of the brush border loss, downregulation of the tubular injury marker, and a reduction in serum creatinine and BUN levels.…”

“…Hesperetin is a natural flavonoid that has antioxidant and anti-inflammatory properties [ 13 , 14 ]. Administration of hesperetin can ameliorate myocardial ischemia [ 15 ], calcific aortic valve disease [ 16 ], fatty liver disease [ 17 ], osteoarthritis [ 18 ], colitis [ 19 ], acute lung injury [ 20 ], and Alzheimer’s disease [ 21 ] in rodents. In addition, hesperetin can alleviate unilateral ureteral obstruction-induced renal injury and fibrosis through inhibiting epithelial–mesenchymal transition in mice [ 22 ].…”