Effects of Calcium, Vitamin D, and Hormone Therapy on Cardiovascular Disease Risk Factors in the Women's Health Initiative

Schnatz, Peter F.; Jiang, Xuezhi; Aragaki, Aaron K.; Nudy, Matthew; O’Sullivan, David; Williams, Mark E.; LeBlanc, Erin S.; Martin, Lisa W.; Manson, JoAnn E.; Shikany, James M.; Johnson, Karen C.; Stefanick, Marcia L.; Payne, Martha E.; Cauley, Jane A.; Howard, Barbara V.; Robbins, John A.

doi:10.1097/aog.0000000000001774

Cited by 20 publications

(8 citation statements)

References 30 publications

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“…The WHI results are similar to those reported by others (11)(12)(13). However, estrogen administered to postmenopausal women increases LDL clearance and lowers the levels of total cholesterol (TC), LDL-C, and apoliprotein B in plasma, showing the beneficial effects of estrogen in reducing the risk of cardiovascular disease (14)(15)(16)(17)(18)(19)(20)(21).…”

Section: Introductionsupporting

confidence: 88%

17β-Estradiol Inhibits PCSK9-Mediated LDLR Degradation Through GPER/PLC Activation in HepG2 Cells

Gao

Zhang

et al. 2020

Front. Endocrinol.

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Plasma levels of PCSK9 are significantly higher in postmenopausal women. Pharmacologically increased estrogen levels have been shown to lower PCSK9 and LDL-C levels in animals and humans. The action of estrogen suggests that it has the ability to prevent PCSK9-mediated LDLR degradation in liver cells. However, little is known about how estrogen alters PCSK9-mediated LDLR degradation. Here, we report that 17β-estradiol (βE2) reduces PCSK9-mediated LDLR degradation by a mechanism that involves activation of the G protein-coupled estrogen receptor (GPER). In cultured HepG2 cells, βE2 prevented the internalization of PCSK9, which subsequently lead to PCSK9-mediated LDLR degradation. The altered LDLR levels also resulted in an increase in LDL uptake that was not observed in the absence of PCSK9. In addition, we showed that clathrin was rapidly increased in the presence of PCSK9, and this increase was blocked by βE2 incubation, suggesting rapid recruitment of clathrin in HepG2 cells. PLCγ activation and intracellular Ca 2+ release were both increased due to the rapid effect of estrogen. By using a GPER antagonist G15, we demonstrated that the GPER mediates the action of estrogen. Together, the data from this in vitro study demonstrate that estrogen can regulate LDLR levels mainly through GPER activation, which prevents PCSK9-dependent LDLR degradation in HepG2 cells.

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Section: Introductionsupporting

confidence: 88%

17β-Estradiol Inhibits PCSK9-Mediated LDLR Degradation Through GPER/PLC Activation in HepG2 Cells

Gao

Zhang

et al. 2020

Front. Endocrinol.

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“…Vitamin D3 is a fat-soluble vitamin that efficiently promotes the absorption and utilization of calcium elements in pregnant women, reduces the metabolism of calcium elements by the kidneys, and helps maintain the blood calcium level in the body [ 21 ]. Wang[ 22 ] et al stated that the detection of blood pressure levels in the maternal organism is effective in preventing the occurrence of hypertensive disorders [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

The Efficacy of Calcium Carbonate-Vitamin D3 in Pregnant Women for the Prevention of Hypertensive Disorders in Pregnancy

Chen

2022

Evidence-Based Complementary and Alternative Medicine

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Objective. To evaluate the efficacy of calcium carbonate-vitamin D3 in pregnant women for the prevention of hypertensive disorders in pregnancy. Methods. Between April 2020 and June 2021, 60 pregnant women undergoing prenatal examinations in our hospital were recruited and assigned via the random number table method at a ratio of 1 : 1 to receive conventional pregnancy care (observation group) or conventional pregnancy care plus calcium carbonate-vitamin D3 administration (experimental group). Outcome measures included blood pressure, blood calcium, the occurrence of hypertensive disorders, and adverse events. Results. The diastolic blood pressure (DBP) and systolic blood pressure (SBP) levels at delivery in the experimental group were significantly lower than those in the observation group ( P < 0.05 ). Pregnant women in the experimental group had significantly higher blood calcium levels at labor than those in the observation group ( P < 0.05 ). The administration of calcium carbonate-vitamin D3 resulted in a significantly lower incidence of hypertensive disorders and adverse events versus conventional pregnancy care ( P < 0.05 ). Conclusion. The effect of calcium carbonate-vitamin D3 administration during pregnancy for the prevention of hypertensive disorders is significant, which effectively improves the blood calcium level of pregnant women and reduces the occurrence of adverse events, so it is worthy of clinical promotion and application.

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“…However, it is worth noting that none of the RCTs were specifically conducted for evaluating the effect of supplemental vitamin D on lipids and lipoproteins. Interestingly, the largest trial (The WHI-Calcium+Vitamin D trial) conducted in 36,282 women showed that patients receiving combined vitamin D and omega-3 fatty acid supplementation had decreased serum very low-density lipoprotein cholesterol and serum triglycerides [42] while 400 IU vitamin D3 plus 1000 mg elemental calcium carbonate daily showed a decrease in LDL cholesterol after 6 weeks of intervention [43]. Consistently, our MR analysis in Chinese adults for the first time showed that each 25 nmol/l genetic increase in 25(OH)D concentration was associated with 0.058 mmol/L(0.22 mg/dL) and 0.034 mmol/L(0.13 mg/dL) lower total and LDL cholesterol, thus suggesting that 25(OH)D may play a causal role in lipid metabolism at least in Chinese adults.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D and cause-specific vascular disease and mortality: a Mendelian randomisation study involving 99,012 Chinese and 106,911 European adults

Huang

Afzal

et al. 2019

BMC Med

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Background Randomised control trials and genetic analyses have demonstrated that vitamin D or 25-hydroxyvitamin D (25[OH]D) levels may not play a causal role in the development of cardiovascular disease. However, it is unclear if 25(OH)D is causally associated with cause-specific vascular disease and lipids. Therefore, we examined the causal association of 25(OH)D with myocardial infarction, stroke, ischaemic heart disease, ischaemic stroke, subarachnoid haemorrhage, intracerebral haemorrhage, and lipid levels among both Chinese and Europeans. Methods We used a Mendelian randomisation (MR) design in the China Kadoorie Biobank, the Copenhagen City Heart Study, and the Copenhagen General Population Study. The 25(OH)D-related genetic variants in the CYP2R1 and DCHR7 genes were genotyped in 99,012 Chinese adults and 106,911 Danish adults. Results In Chinese adults, plasma 25(OH)D levels were not significantly associated with cause-specific vascular disease or mortality, with the exception of intracerebral haemorrhage (HR, 1.09 [95% CI, 1.01,1.18] per 25 nmol/L higher plasma 25(OH)D). In Europeans, plasma 25(OH)D levels were inversely associated with all types of vascular diseases and mortality. However, MR analysis did not demonstrate causal associations of genetically increased 25(OH)D levels with cause-specific vascular diseases, or mortality in both Chinese and European adults. In addition, each 25 nmol/L higher 25(OH)D was observationally associated with lower total cholesterol and low-density lipoprotein cholesterol levels, but higher high-density lipoprotein cholesterol levels. Likewise, MR analysis showed that 25(OH)D levels were not causally associated with lipids in both Chinese and European adults after Bonferroni correction. Conclusions We found no evidence to support that genetically increased 25(OH)D was associated with a lower risk of ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and lipid levels in both Chinese and European adults. These results suggest that the inverse associations of vitamin D with vascular disease could be the result of confounding. Electronic supplementary material The online version of this article (10.1186/s12916-019-1401-y) contains supplementary material, which is available to authorized users.

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Effects of Calcium, Vitamin D, and Hormone Therapy on Cardiovascular Disease Risk Factors in the Women's Health Initiative

Cited by 20 publications

References 30 publications

17β-Estradiol Inhibits PCSK9-Mediated LDLR Degradation Through GPER/PLC Activation in HepG2 Cells

17β-Estradiol Inhibits PCSK9-Mediated LDLR Degradation Through GPER/PLC Activation in HepG2 Cells

The Efficacy of Calcium Carbonate-Vitamin D3 in Pregnant Women for the Prevention of Hypertensive Disorders in Pregnancy

Vitamin D and cause-specific vascular disease and mortality: a Mendelian randomisation study involving 99,012 Chinese and 106,911 European adults

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