This study showed that SIRT1 concentrations, which do not increase from 4 weeks of gestation up to > 20 weeks, elevate the probability of developing preeclampsia, including early onset, late-onset, or postpartum preeclampsia. It demonstrates that termination of pregnancy through placental removal is not a single accomplishment to inhibit the development of preeclampsia as well as reported in previous studies [23, 24], and postpartum preeclampsia in our finding has a higher serum SIRT1 concentration than early-onset or late-onset preeclampsia. The incidence of postpartum preeclampsia generally occurs in women with antenatal hypertension, which is a disease entity that has not been extensively studied [25]. Widely, endothelial dysfunction is referred to as the primary determinant of preeclampsia progression, through driving various mechanisms to vascular function damage and peripheral resistance, which are associated with the development of hypertension [26, 27]. Literature indicates that SIRT1 is one of the plausible mechanisms that protect against endothelial dysfunction, vascular disease, and sustained cell survival [28, 29]. SIRT1 functional downregulation leads loss of endothelial cells' ability to produce nitric oxide (NO) which reflects an early process of cardiovascular pathology, including hypertension [30–34]
A recent study reported that SIRT1 has a central role in inhibiting cell death through deacetylation of p53, thereby increasing the degradation of p53 as a tumor suppressor gene, and can reduce the capacity that mammalian forkhead transcription factors of the O class (FOXO3) to induce cell cycle arrest, resulting in resistance to oxidative stress. Additionally, SIRT1 can also prevent inflammation-induced cytotoxicity via the NFkB deacetylation pathway [35–37]. Our study also showed that low-density lipoprotein (LDL), an essential source of systemic oxidative stress and immunoinflammatory response significantly associated with serum SIRT1 concentration. In general, increasing cholesterol levels, mainly LDL, which is atherogenic, can provoke inflammation with related action of monocyte in the endothelium leading to vascular wall dysfunction through different signaling pathways associated with inflammation, particularly SIRT1 [38, 39]. In Addition, we found that diastolic blood pressure (DBP) was significantly related to serum SIRT1 concentration in pregnant women with moderate and high-risk factor-related preeclampsia. This is followed by prior research that SIRT3 deficiency also impaired the blood pressure and diastolic function of animal models [40]. However, the molecular mechanism of these alterations remains unclearly. Interestingly, diastolic dysfunction in aging often presents endothelial dysfunction and vascular tone dysregulation. On the other hand, Body Mass Index (BMI) and age were frequently reported as influence factors of SIRT1 reduction [41, 42] but did not show a significant correlation in the present study.
Corroborating with our result, prior research reported that SIRT1 plasmatic level was reduced in preeclampsia compared to healthy pregnancy and gestational hypertensive pregnancy in vitro (p < 0,001) [31], another study showed that SIRT1 mRNA expression is reduced in PE placenta compare normal pregnancy (p < 0,001) [43]. Adjacent to previous research, we provide extending results that lowering plasmatic SIRT1 concentration, discovery with a similar pattern in serum SIRT1 profile and SIRT1 expression in the placenta suggest that SIRT1 has directly involved in the pathomechanism of preeclampsia. At least, there are two plausible mechanisms involved in the SIRT1 pathway, (i) Downregulation of SIRT1 in maternal circulation may contribute to trophoblast senescence and impaired invasion ability to the spirals arterial, generate uteroplacental disorders sequentially with placental hypoxia [44; 18]. Furthermore, elevating antiangiogenic factors production as a result of placental hypoxia leads to the vascular endothelial growth factor (VEGF) signaling disruption followed by massive damage to vascular endothelial cells. Another plausible mechanism is (ii) Risk factors for preeclampsia in pregnant women may probably be major contributors to the presence of maternal endothelial dysfunction which worsens with pregnancy. It is well known that the placenta is the main source of angiogenic factors production such as soluble Fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) that disrupt VEGF signaling, as a regulator of vascular endothelial cell viability [45, 46]. Thus even a small increase in antiangiogenic factors may exacerbate preexisting maternal endothelial dysfunction in women with persistent preeclampsia risk factors.
The novelty of this study showed that pregnant women who have risk factors associated with preeclampsia may experience suboptimal enhance serum SIRT1 concentrations from the 4th to the 20th week of gestation. To our knowledge, this is the first study looking at the association between serum SIRT1 concentration and preeclampsia through a long-term cohort study from early pregnancy to the postpartum period. One of the limitations is that this study was performed in one area, i.e., Tulungagung, limiting the generalizability of the findings. However, there are still many questions that required further experimental validation. Upcoming research should distinguish an expanding model to manage women with risk factors to promote SIRT1 profile elevation for pregnancy outcomes improvement including the possible inhibiting risk of fetal asphyxia or the development of manifestations of early onset cardiovascular disease (CVD). These issues still require further study and clinical trials to advance verification, which is also the heading of our intended research.