It is well recognized that hypertension increases the risk of a number of illnesses, including heart failure, renal failure, stroke, disability, and early death [
30]. A number of pathophysiological changes brought on by hypertension may harm the retinal, choroidal, and optic nerve circulations, resulting in retinopathy, choroidopathy, and optic neuropathy, in that order, in the eyes [
2,
31,
32]. During the first phase, the retinal arterioles undergo vasoconstriction and localized vasospasm in response to high blood pressure. The local autoregulatory systems responsible for optimizing blood flow are the cause of the vasospasm. The clinical manifestation of these occurrences is a reduction in the normal arteries to vein ratio, which indicates either localized or global constriction of the retinal arteries. Over time, high blood pressure causes structural alterations in the arterial wall, including hyaline degeneration, mediawall hyperplasia, endothelial damage, and intimal thickening. This phase causes the vessel walls' focused or diffuse light response to be emphasized, as well as a shift in arteriovenous crossing or nicking [
33‐
35].
In many disorders, the NLRP3 inflammasome is important in controlling the immune system's inflammatory reactions [
5]. According to recent research, individuals with hypertension consistently have elevated plasma levels of NLRP3 [
36]. The pro-inflammatory kind of cell death known as pyroptosis, which is brought about by NLRP3 activation, exacerbates the inflammatory response by causing the release of IL-1β and other pro-inflammatory intracellular components [
37]. Vascular dysfunction and pro-inflammatory cytokine levels may be correlated [
38]. Moreover, cytokine levels, including as
Tnf, Il6, and
Il1b, are downregulated when the NLRP3 inflammasome is inhibited [
39]. It is advantageous to inhibit the NLRP3 inflammasome in order to lessen inflammation and the pathological alterations that follow from inflammation [
7].
Our research revealed that Ang II infusion may increase the expression of NLRP3 and reduce the level of SIRT1 (Fig.
1); these findings showed that Ang II-induced hypertensive retinopathy and dysfunction may involve both SIRT1 and NLRP3. Next, we administered MCC950, an NLRP3 inhibitor, to the mice. Following MCC950 therapy, we observed that NLRP3 and IL-1β expression were suppressed, and that in Ang II-infused animals, NLRP3 suppression reduced retinopathy and dysfunction (Figs.
2,
3). In order to examine SIRT1's function in the Ang II-induced NLRP3 inflammasome and HR, we administered SIRT1 agonist, SRT1720, to the mRECs. The data in Fig.
4 demonstrated how Ang II-induced NLRP3 inflammasome activation and ROS generation are inhibited by SIRT1 overexpression. As a sensor and defender of the redox environment, SIRT1 is involved in the control of cell survival, apoptosis, and inflammation [
40]. It is a NAD-dependent deacetylase that controls how proteins function through lysine residue deacetylation. According to a publication, SIRT1 prevents NLRP3 inflammasome-induced IL-1β production, therefore shielding mesenchymal stem cells from radiation damage [
41]. SIRT1 may also deacetylate NF-κB to promote the suppression of NLRP3 inflammasome activation [
7]. Inflammation and cell pyroptosis linked to the NLRP3 inflammasome are negatively regulated by SIRT1, and this has an impact on avoiding Ang II-induced HR and malfunction. Furthermore, p53, another transcription factor that targets apoptosis-associated speck-like protein containing a CARD (ASC), which is necessary for NLRP3 inflammasome assembly, was affected by SIRT1's diverse deacetylase activity [
42]. Thus, it is plausible that SIRT1 acted as an upstream regulator of the activation of the NLRP3 inflammasome produced by Ang II in conjunction with the current investigation. SIRT1 overexpression could significantly decrease the inflammasome activation. In our present study, we found FO could inhibit apoptosis and improve cardiac remodeling by inhibiting tumor suppressor protein (p53) transcriptional activation through ubiquitin-specific protease (USP22)—SIRT1 [
24]. FO mainly extracted from brown algae is a fucose-enriched sulfated polysaccharide, and it has been widely used as a dietary supplement and health food due to its numerous beneficial effects, including anti-inflammatory, anticancer, and antidiabetic activities [
18]. Recent studies have found that FO reduced secretion and expression of vascular endothelial growth factor in the retinal pigment epithelium and reduced angiogenesis in vitro [
43]. Fucoidan is currently considered a functional food, but is also investigated in clinical trials [
44]. Its effects have been studied not only in vitro, but also in animal and human studies, were it exhibits an excellent toxic profile. While its oral availability is under debate, recent studies indicate a possible absorption of fucoidan by the gastrointestinal tract, which would render an oral application an attractive alternative to intravitreal injections [
29]. In our study, we found FO enhanced SIRT1 expression and reduced NLRP3 activation and retinopathy and dysfunction in Ang II-treated mice and mRECs (Fig.
5–
7). This approach provides a potential targeted strategy to treat HR and dysfunction. But we have some limitations, one potential drawback is the study's applicability to human populations, which could be addressed by discussing any known similarities and differences in the SIRT1 and NLRP3 inflammasome pathways between mice and humans. Future research could focus on the exploration of the SIRT1/NLRP3 pathway in other models of hypertensive organ damage, and translation into clinical research. The clinical significance would be more compelling if it included functional endpoints that mirror human disease, such as vision acuity or electrophysiological assessments of retinal function.