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Protective cardiovascular and renal actions of vitamin D and sex hormones – June 2013


Protective cardiovascular and renal actions of vitamin D and estrogen.
Front Biosci (Schol Ed). 2013 Jan 1;5:134-48.
Gangula PR, Dong YL, Al-Hendy A, Richard-Davis G, Montgomery-Rice V, Haddad G, Millis R, Nicholas SB, Moseberry D.
Departments of Physiology, Meharry Medical College, Nashville, TN 37208, USA. pgangula at mmc.edu

Both basic science and clinical studies support the concept that vitamin D deficiency is involved in the pathogenesis of cardiovascular and renal diseases through its association with diabetes, obesity, and hypertension. Understanding the underlying mechanisms may provide a rationale for advocating adequate intake of vitamin D and calcium in all populations, thereby preventing many chronic diseases. This review explores the effect of vitamin D deficiency in the development of cardiovascular and renal diseases, and the role of vitamin D supplementation on cardiovascular outcomes. In addition, it highlights the importance of vitamin D intake for the prevention of adverse long-term health consequences, and in ways to facilitate the management of cardiovascular disease. This is particularly true for African American and postmenopausal women, who are at added risk for cardiovascular disease. We suggest that the negative cardiovascular effects of low vitamin D in postmenopausal women could be improved by a combined treatment of vitamin D and sex steroids acting through endothelium-dependent and/or -independent mechanisms, resulting in the generation of nitric oxide and calcitonin gene-related peptide (CGRP).

PMID: 23277041

The following sections are clipped from the PDF is attached at the bottom of this page

4. SEX HORMONES AND CARDIOVASCULAR DISEASE

The metabolic syndrome represents a specific clustering of cardiovascular risk factors including obesity. It is highly prevalent in the United States, and currently affects approximately one in four adults. Hypertension in women increases fourfold the risk of subsequent cardiovascular disease, and leads to approximately 35% of all cardiovascular events (53). The presence of hypertension has a significantly greater effect on CHD in women than in men. African Americans-especially AA women- appear to be particularly predisposed to the development of the metabolic syndrome. AAs also have the highest mortality rate due to CHD of any ethnic group (54). Reports indicate that AAs have a 3-to-5-times higher cardiovascular mortality rate compared to whites (55). Although the exact mechanisms for developing this disease are not known, reduced levels of sex steroid hormones such as estrogens and/or vitamin D may be responsible for the increased CHD in this population (56). Others have shown a link between vitamin D and estrogens in the vasculature suggesting that these two factors both independently or inter-dependently regulate cardiovascular functions and normalize blood pressure via several endogenous potent vasodilators including prostaglandins (PGs), nitric oxide (NO) and calcitonin gene related peptide (CGRP) (57) (Figures 1-2). For example vitamin D or estradiol supplementation improves vascular NO and regulates blood pressure (58). Recent studies indicate that the enzymes responsible (59) for vitamin D synthesis are colocalized with calcitonin gene related peptide containing neurons (I-CGRP) in the dorsal root ganglia. We and others have demonstrated that the vascular protective effects of sex steroid hormones, namely estradiol-17beta and progesterone, involve CGRP (60). However, it is unclear whether sex hormones and/or vitamin D regulate the blood pressure directly or indirectly and if so, what molecular mechanisms are involved. Sun exposure, as an indirect index of vitamin D skin synthesis, has been reported to be inversely associated with blood pressure and the prevalence of hypertension. In addition, ultraviolet light exposure lowers blood pressure. This further supports the fact that estrogen receptors, vitamin D receptors (VDR) and the enzyme, 1-alpha-hydroxylase (1alpha-OHD), a key enzyme for vitamin D synthesis, are present in the vasculature. Further the decrease in vascular 1alpha-OHD and VDR (Figures 3, 4) in female FORKO (follicle stimulating hormone receptor knockout) mice, a model of hypertension and menopause, was associated with a reduction in neuronal NO synthase (nNOS) dimerization as well as a reduction in CGRP receptor components such as CRLR and RAMP1 (Figures 5-7). This data further support the hypothesis that a cross-talk between sex hormones and vitamin-D may play a pivotal role in regulating vascular functions, particularly in women.
An increased activation of the RAAS plus endothelial dysfunction has been suggested as contributors to the development of hypertension (61). Vitamin D supplementation may protect subjects from hypertension by suppressing RAAS, restoring endothelial dysfunction, and reversing effects on calcium metabolism, including prevention of secondary hyperparathyroidism Specifically, supplementation with vitamin D has been shown to improve endothelial function in patients with type 2 diabetes (63). Unpublished studies from our laboratory indicate that non-calcemic 3-epi-isomer-vitamin D3 is more potent than 1,25 OH2D3 (known to possess high calcemic properties) in restoring reduced endothelial nitric oxide synthase (eNOS) dimerization in hyperglycemic human umbilical vascular endothelial cells (HUVEC) in-vitro. These data suggest that non-calcemic vitamin D analogs may be safe and useful in improving altered NO and thus control endothelial function at least in diabetic patients. Both VDR and 1 alpha-hydroxylase knock-out mice develop hypertension and myocardial hypertrophy (64). In addition, supplementation with vitamin D attenuates both the elevated blood pressure and impaired vascular relaxation in response to acetylcholine in spontaneous hypertensive rats (65). Finally, both endothelium-dependent and endothelium-independent vascular relaxation has been shown to be impaired in AA compared to non-AA subjects (66). Taken together, the above literature thus far suggests that the lower vitamin D levels observed in the AA population may potentially be related to impaired RAAS as well as abnormalities in vascular relaxation which may provide a link to the development of hypertension.
There are substantial gender differences in the incidences of hypertension, heart failure and coronary artery disease. The main risk factors for heart failure and coronary artery disease are diabetes and hypertension in both men and postmenopausal women (67). Ventricular and vascular stiffening (68), atrial fibrillation with hypertension and dilated cardiomyopathy (69) and drug induced prolongation of the electrocardiogram QT interval (70) were reported to occur more often in women than in men and the reverse was true for ischemic heart disease (71). Estrogen and testosterone were reported to have rapid nongenomic effects on ion channels and sarcolemmal currents (72), and their receptors were found to be colocalized in vascular smooth muscle and endothelial cells (73). Interactions between estrogen related receptors and other nuclear receptors such as the peroxisome proliferator activated receptors (PPARS) (74), as well as estrogen, testosterone and other sex steroids with gene loci on the X-chromosome may contribute to the male and postmenopausal predilections for cardiovascular disease and to the protection thought to be afforded by estrogen in premenopausal women.

5. SEX HORMONES AND RENAL DISEASE

Epidemiological studies show that men progress faster to end stage renal disease when they have conditions such as hypertensive glomerulosclerosis, polycystic kidney disease, or autoimmune glomerulonephritis. Even an age-related renal decline is faster in men than women, although women begin catching up after menopause (75). The mechanisms of action by which sex steroids prevent renal injury are multifactorial.

5.1. Sex hormones and the glomerular capillary pressure

Estradiol is thought to be renoprotective in part by decreasing the mitogenic effects of multiple growth factors that participate in glomerulosclerosis (76). Although the mechanism of action is unclear, it is felt that sex steroid-induced differences in glomerular capillary pressure may play a role. When men and women were both given an infusion of angiotensin (Ang) II, both groups had a similar response; there was an increase in blood pressure and a decrease in the effective renal plasma flow. However the resultant increase in estimated glomerular filtration rate (eGFR) was only maintained in men. In women the eGFR declined in parallel with the effective renal plasma flow and there was no increase in filtration fraction (FF). It can be surmised that the Ang II mediated increase in glomerular capillary pressure was greater in males than in females, and that the resultant increase in FF could lead to renal injury (75).
It is well established that inhibition of the RAAS delays the progression of renal disease. Testosterone may promote renal injury by stimulating the production of Ang II (75). In contrast estrogen decreases the angiotensin type 1 receptor (AT1) in many tissues including kidney. In addition estrogen increases angiotensinogen levels, and decreases plasma renin levels. The findings of the Women's Health Initiative suggest these changes are lost after menopause (75).

5.2. Estradiol and testosterone effects on oxidative stress

There is also evidence that oxidative stress is linked to renal diseases such as drug-induced nephrotoxicity, IgA nephropathy (77), ischemia-reperfusion injury (78) and diabetic nephropathy (79). Estradiol is an antioxidant, while androgens appear to increase oxidative stress as evidenced by the fact that in human studies, men have higher levels of indicators of oxidative stress than age matched premenopausal women (80).
Recent reports demonstrated a synergistical role of 1, 25-dihydroxyvitamin D (3) and 17beta-estradial in proliferation and differentiation of osteoblasts, and this coordinated regulation might depend on the upregulation of vitamin D receptor in osteoblasts by 17beta-estradial. (81) Studies also suggested that increased androgenicity, characterized by high testosterone and low SHBG levels, is associated with an adverse CVD risk factor profile in postmenopausal women. (82)

5.3. Estradiol and the endothelial system

There is a paucity of data about the interaction of the sex hormones and the endothelial system. Since estradiol can down regulate AT1 receptor expression, it theoretically should increase endothelial markers such as NO and protect against renal injury, however such studies have not been performed (75). Estrogens play a pivotal role in a large number of physiological processes, including the cardiovascular system. Both acetylcholine-induced and flow-dependent vasodilation are preserved or potentiated by estrogen treatment in both animal models and humans. (83) E2 increases the endothelial production of nitric oxide and prostacyclin and prevents early atheroma through endothelial-mediated mechanisms. Furthermore, estrogens promote endothelial healing, as well as angiogenesis. Estrogen actions are essentially mediated by 2 molecular targets: estrogen receptor-alpha (ER-alpha) and ER-beta. An analysis of mouse models targeting ER-alpha or ER-beta demonstrated a prominent role of ER-alpha in vascular biology.

6. SEX HORMONES AND DIABETES

Results from a large clinical trial of 27,805 patients with type I diabetes mellitus indicated that the male sex was an independent risk factor associated with the development of CKD. In this study the female protective effect was lost in the presence of diabetes. There was also no gender difference in the development of CKD in patients with the metabolic syndrome (75).

7. REPLACEMENT STRATEGIES AND OUTCOMES

7.1. Vitamin D replacement and renal disease

Abnormal bone mineral metabolism with bone pain and osteodystrophy is present in all patients with stage 5 CKD. Severe osteodystrophy is less common in the earlier stages of CKD, but an elevation of parathyroid hormone, measured by intact parathyroid hormone (iPTH) levels has been reported (84-92). The K/DOQI guidelines recommend routine measurement of iPTH, phosphorous and calcium to manage and prevent metabolic bone disease (50). For patients with an elevated iPTH, the 25-OHD level should be assessed and replaced if a vitamin D deficiency (serum 25-OHD levels <30 ng/ml) is identified. Muntner et al(90) analyzed NHANES data for iPTH levels, and noted that iPTH levels were higher and vitamin D levels lower in < stage 3 CKD. The 25-OHD level reduction caused a compensatory increase in iPTH in persons with normal renal function. Therefore reversing a vitamin D deficiency reduced the frequency of secondary hyperparathyroidism and metabolic bone disease (90). Consequently, vitamin D supplementation may be necessary to prevent these diseases.
A double blind, randomized, placebo controlled trial to evaluate the safety of paricalcitol in CKD stages 3 and 4 was conducted. In a subset of 118 patients that had baseline proteinuria, the odds of a reduction of proteinuria was 3.2 times greater (95% CI 1.5-6.9) for oral paricalcitoltreated patients than for placebo patients (93). Of the 57 paricalcitol patients, 29 (51%) had a reduction in proteinuria compared to only 15 of the 61 (25%) placebo patients (P=0.004). This suggests that vitamin D may possibly be important in maintaining the structural integrity of the kidney. More studies need to be done using less costly vitamin D preparations to evaluate if they are equally effective in reducing proteinuria.
It is recommended that patients with stage 5 CKD be treated with activated vitamin D. Older preparations, calcitriol and alfacalcidol, have been associated with increased serum calcium and phosphorus levels. Calcium and phosphorus elevations may cause calcification in the arteries and tissues. Newer preparations, including paricalcitol and doxecalciferol are supposed to reduce stimulation of parathyroid hormone in CKD patients but not appreciably increase calcium and phosphorus levels. The Cochrane Collaborative study did a metanalysis of 60 studies and found that patients receiving the older activated vitamin D compounds were not at increased risk of developing hypercalcemia or hyperphosphaturia (94). In those few studies that did see these changes, the results did not reach statistical significance. To the contrary, newer compounds were associated with more hypercalcemia (94).

7.2. Estrogens and progestins

It is well recognized that postmenopausal women of all ethnicities exhibit higher incidences of hypertension, heart failure and coronary artery disease than premenopausal women and that these outcomes can be explained by estrogen deficiency, although there is renewed interest in the related role of androgens (95). It is unclear whether deficiencies in estrogen synthesis, estrogen receptor expression or estrogen-related functional changes, some perhaps related to functions of the RAAS, contribute to the effects of postmenopausal estrogen deficiency (96). Postmenopausal women could be at higher risk for coronary artery disease because of lower plasminogen activator inhibitor-1 (PAI1) levels. PAI1 levels are reported to be correlated with lower plasma levels of estrogen and lower PAI-1 levels are reported to be associated with hypertension and heart failure, thereby suggesting that PAI1 may serve as a useful biomarker for the risk of cardiovascular disease (73). Cardiomyocytes express G-protein coupled estrogen receptors which are reported to decrease cardiac sarcolemmal K+ currents (97), prevent cardiac fibrosis (98) and provide cardioprotection from ischemia reperfusion injury (99). Knockout mice lacking the G-coupled estrogen receptor-2 exhibit systemic hypertension as well as right and left ventricular hypertrophy (100, 101). Estradiol-induced stimulation of G-protein coupled estrogen receptors resulted in cGMP mediated phosphorylation and inactivation of calcium-activated K+ channels in human coronary artery myocytes independent of the endothelium (102), known mechanisms related to NO-mediated vascular smooth muscle relaxation. Regions of human atherosclerotic plaques had higher rates of DNA methylation of the promoter region of the estrogen-beta receptor gene than non-atherosclerotic regions (103), suggesting a role for epigenetic mechanisms. In normotensive experimental animals, estrogens were shown to relax coronary artery smooth muscle (104) by superoxide-mediated (105), NO-mediated and protein kinase C related mechanisms (106). Paradoxically, the estrogen receptor antagonist tamoxifen also appeared to relax coronary artery smooth muscle by an endothelium, NO-dependent mechanism (107). On the other hand, attenuation of vascular smooth muscle relaxation is shown to occur in spontaneously hypertensive female rats (108). In humans, hormone replacement therapy with estrogen is reported to be associated with adverse cardiovascular events (109). Ethinyl estradiol and some progestins were reported to activate the RAAS (110).

7.3. Androgens: testosterone and dehydroepiandrosterone (DHEA)

Testosterone antagonizes vascular smooth muscle relaxation produced by adenosine, thereby increasing vascular resistance (111). Although the mechanisms remain unclear, the low coronary blood flow associated with high LDL, high VLDL and low HDL levels correlated with the risk for development of systemic hypertension and heart failure. High pulse pressure is shown to be inversely correlated with penile blood flow and to be a predictor of low plasma testosterone, erectile dysfunction and coronary artery disease (112). Low blood flow to medullary vasomotor centers has been proposed as a mechanism for essential hypertension (113) and perhaps chronic renal disease. Low plasma testosterone and high estradiol are reported to be associated with development of the metabolic syndrome triad of obesity, diabetes and hypertension (114). The presence of a vertex pattern of androgenic alopecia appears to be a correlate of the metabolic syndrome and atherosclerosis in men and successful treatment with finasteride suggested involvement of an increased activity of 5-alpha reductase as an important mechanism (115). In young women, high plasma testosterone levels are associated with high incidences of coronary artery disease (116). In women with polycystic ovary syndrome, plasma testosterone appears to be positively correlated with systemic blood pressure (117). Recent studies demonstrated large beneficial effects of DHEA administration on Mental Rotation, Subject-Ordered Pointing, Fragmented Picture Identification, Perceptual Identification, and Same-Different Judgment.(118) Moreover, DHEA administration enhanced serum levels of DHEA, DHEAS, testosterone, and estrone, and regression analyses demonstrated that levels of DHEA and its metabolites were positively related to cognitive performance on the visual-spatial tasks in the DHEA condition.
The incidence of chronic renal diseases is associated with postmenopausal loss of, and is improved by treatment with estrogen (119). The precursors for estrogens are the androgenic hormones testosterone and DHEA and low DHEA levels were reported to be associated with endothelial dysfunction, renal injury and increased cardiovascular mortality, thereby providing a rationale for DHEA supplementation in postmenopausal women (120). Administration of DHEA to ovariectomized rats protected against hypertension-induced kidney injury via upregulation of the sigma-1R receptor and stimulation of Akt-eNOS signaling (121).

7.4. Oxytocin

Modulations in expression of oxytocin and its receptors may also contribute to various predilections for hypertension, heart failure and coronary artery disease. Decrements in oxytocin receptor activity are reported to contribute to cardiac pathology by decreases in left ventricular ejection fraction and increases in collagen content, indicative of fibrosis (122). Oxytocin receptors have been demonstrated in cardiomocytes (123) and in the capillary endothelium expressing CD31 colocalized with NO (124). In ovariectomized spontaneously hypertensive rats, genistein-stimulated increases in synthesis of oxytocin receptors were reported to be associated with decrements in mean arterial blood pressure, heart weight, collagen content and brain natriuretic peptide (122).
A randomized, double-blind, placebo-controlled trial was conducted at three Italian university medical centers to assess the effects of the administration of the phytoestrogen genistein (54 mg/d) on some predictors of cardiovascular risk in osteopenic, postmenopausal women (125). The results suggested that 54 mg genistein plus calcium, vitamin D3, and a healthy diet was associated with favorable effects on both glycemic control and some cardiovascular risk markers in a cohort of osteopenic, postmenopausal women.
Studies exploring the effect of calcium intake or calcium supplementation on cardiovascular risk suggest that systolic blood pressure increases under low calcium intake and decreases with calcium supplementation (126). A lower calcium intake has been associated with an increased risk of stroke. Negative correlations between vitamin D levels and the risk of hypertension, myocardial infarction, and stroke have been reported in several observational studies. However, there is a lack of randomized clinical trials primarily addressing the effect of these parameters on CVD. Therefore, the real impact of calcium and vitamin D on cardiovascular outcomes remains to be documented by appropriate experimental data.

8. PERSPECTIVE

Metabolic syndrome represents a specific clustering of cardiovascular risk factors including obesity. Several lines of evidence suggest that overweight and diabetes are most common cause of hypertension and gastroparesis due to at least in part due to impairment in vascular as well as stomach nitric oxide system. Metabolic syndrome is highly prevalent in the United States, and currently affects approximately one in four adults. Hypertension in women increases the risk of subsequent cardiovascular disease by fourfold, and leads to approximately 35% of all cardiovascular events (53). The presence of hypertension has a significantly greater effect on CHD in women than in men.

African Americans-especially AA women appear to be particularly predisposed to the development of the metabolic syndrome. AAs also have the highest mortality rate due to CHD of any ethnic group (54). Reports indicate that AAs have a 3-to-5-times higher cardiovascular mortality rate compared to whites (55). Although the exact mechanisms for developing this disease are not known, reduced levels of sex steroid hormones such as estrogens and/or of vitamin D may be responsible for the increased CHD in this population (56). Others have shown a link between vitamin D and estrogens in the vasculature suggesting that these two factors both independently or inter-dependently regulate cardiovascular functions through their receptors and normalize blood pressure via several endogenous potent vasodilators including Pgs, nitric oxide NO and CGRP (57).
It is evident that vitamin D improves eNOS expression in vascular cells and that vitamin D metabolizing enzymes appear to be colocalized with I-CGRP neurons in the dorsal root ganglia. Sex steroid hormones, in particular estradiol-17beta and/or soy isoflavones (estrogenic compounds), regulate eNOS- or nNOS-mediated neuroendocrine and vascular smooth muscle function through the NMDA (N-methyl-D-aspartate) receptor channels, calcium/calmodulin and HSP-90 signaling. On the other hand, sex steroid hormones regulate cardiovascular functions via endothelium-independent mechanisms such as CGRP. Our findings including others support the existing hypothesis that sex steroid hormones and vitamin D may regulate renocardiovascular as well as gut motility functions through a number of mechanisms including NO and CGRP. Large clinical trials are needed to unravel the beneficial effects of natural hormones/activation of hormone receptors, and/or vitamin D/VDR analogs on the kidneys, blood pressure and rest of the body, and to determine their place in the treatment of menopause.


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