Abolition of End-Organ Damage by Antiandrogen Treatment in Female Hypertensive Transgenic Rats

Background: Conditions of excess androgen in women, such as polycystic ovary syndrome (PCOS), often exhibit intergenerational transmission. One way in which the risk for PCOS may be increased in daughters of affected women is through exposure to elevated androgens in utero. Hyperandrogenemic conditions have serious health consequences, including increased risk for hypertension and cardiovascular disease. Recently, gut dysbiosis has been found to induce hypertension in rats, such that blood pressure can be normalized through fecal microbial transplant. Therefore, we hypothesized that the hypertension seen in PCOS has early origins in gut dysbiosis caused by in utero exposure to excess androgen. We investigated this hypothesis with a model of prenatal androgen (PNA) exposure and maternal hyperandrogenemia by single-injection of testosterone cypionate or sesame oil vehicle (VEH) to pregnant dams in late gestation. We then completed a gut microbiota and cardiometabolic profile of the adult female offspring. Results: The metabolic assessment revealed that adult PNA rats had increased body weight and increased mRNA expression of adipokines: adipocyte binding protein 2, adiponectin, and leptin in inguinal white adipose tissue. Radiotelemetry analysis revealed hypertension with decreased heart rate in PNA animals. The fecal microbiota profile of PNA animals contained higher relative abundance of bacteria associated with steroid hormone synthesis, Nocardiaceae and Clostridiaceae, and lower abundance of Akkermansia, Bacteroides, Lactobacillus, Clostridium. The PNA animals also had an increased relative abundance of bacteria associated with biosynthesis and elongation of unsaturated short chain fatty acids (SCFAs). Conclusions: We found that prenatal exposure to excess androgen negatively impacted cardiovascular function by increasing systolic and diastolic blood pressure and decreasing heart rate. Prenatal androgen was also associated with gut microbial dysbiosis and altered abundance of bacteria involved in metabolite production of short chain fatty acids. These results suggest that early-life exposure to hyperandrogenemia in daughters of women with PCOS may lead to long-term alterations in gut microbiota and cardiometabolic function.

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“…Support for this possibility is provided by previous studies in which antiandrogenic treatment attenuated cardiac hypertrophy. 110 , 111 …”

Section: Discussionmentioning

confidence: 99%

Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis

et al. 2018

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“…8 Indeed, androgens are thought to mediate the expression of hypertension in this model. 10 In this regard, Baltatu et al 21 recently reported that the androgen antagonist flutamide reduced blood pressure as well as attenuated the development of cardiac and renal injury in female (mRen2)-27 transgenics. The influence of androgen blockade in the mRen (2).Lewis rat is currently not known.…”

Section: Discussionmentioning

confidence: 99%

Estrogen or the AT1 Antagonist Olmesartan Reverses the Development of Profound Hypertension in the Congenic mRen2.Lewis Rat

et al. 2003

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Abstract-The influence of estrogen on the regulation of cardiovascular function remains a controversial and complex area of investigation. We assessed the effects of estrogen depletion in the congenic mRen(2).Lewis rat, established from the back-cross of the original (mRen2)-27 transgenic onto the Lewis inbred strain. Ovariectomy of heterozygous mRen(2).Lewis at 4 to 5 weeks resulted in a progressive increase in blood pressure compared with the sham surgery congenics at weeks 6 to 11. At 11 weeks, the ovariectomized mRen(2).Lewis (OVX) systolic blood pressure averaged 195Ϯ3.7 mm Hg versus 141Ϯ4.0 mm Hg for sham. Plasma Angiotensin (Ang) II, serum ACE activity, plasma renin concentration, as well as urinary excretion of Ang II, 8-isoprostane F 2␣ , and endothelin-1 were elevated; however, renal mRNA levels of eNOS were suppressed after ovariectomy. Estrogen replacement reduced blood pressure below both the sham and OVX by 11 weeks (125Ϯ2.9 mm Hg, nϭ7, PϽ0.01 versus OVX and sham). Moreover, the AT 1 receptor antagonist olmesartan (CS866; week 12 to 16) essentially normalized blood pressure to 113Ϯ5.4 mm Hg (nϭ6, PϽ0.01 versus OVX and sham). The attenuation of the hypertension was still evident 7 weeks after complete withdrawal of treatment (124Ϯ4.1 mm Hg at week 23). In summary, the OVX mRen.2.Lewis exhibited a rapid and sustained increase in blood pressure. Estrogen or olmesartan lowered pressure by a similar extent. We conclude that the ovary exerts considerable influence on the regulation of the blood pressure in the mRen2. Key Words: angiotensin II Ⅲ angiotensin-converting enzyme Ⅲ estrogen Ⅲ rats, transgenic Ⅲ hypertension, genetic I t is well recognized that ovarian hormones, particularly estrogen, exhibit a protective role on the cardiovascular system. After menopause, there is increased arterial pressure and higher rates of hypertension, renal disease, cardiovascular events, and mortality rates in women. However, recent clinical studies have questioned the beneficial effects of hormone replacement therapy (estrogen/progestin), particularly the actions that influence the cardiovascular system. 1 Indeed, one arm of the Women's Health Initiative (WHI) study with the combined therapy was halted prematurely because of negative outcomes, although the estrogen replacement group has continued at the present time. In light of the clinical data, the protective actions of estrogen would appear to be in contrast to the hormone's effects on several components of the renin-angiotensin system (RAS)-one of the key regulatory systems for the control of blood pressure and cardiovascular pathologies. Specifically, estrogen stimulates the expression of angiotensinogen from the liver, kidney, and other tissues, as well as increases renin activity. 2,3 However, estrogen has also been shown to suppress components of the RAS, including ACE and the AT 1 receptor, perhaps achieving an overall balance to attenuate the development of hypertension and progression of other cardiovascular events. 4 -7 Various hypertensive models have...

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“…Mechanisms References Likewise, there is evidence that antiandrogen treatment of hypertensive rats with flutamide decreases end-organ damage in heart and kidneys 55 ; however, the interpretation of these data are not clear cut, because flutamide has also been found to have cardiovascular actions that are androgen receptor independent. 56 In vitro, androgens have been reported to induce apoptosis in cardiomyocytes.…”

Section: Mechanisms Possibly Involved In the Cardioprotective Effectsmentioning

confidence: 99%

Hypertensive Cardiac Remodeling in Males and Females

Deschepper

Llamas²

2007

Hypertension

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C ardiovascular diseases affect women and men differently: there are sex-dependent differences in the age at which they become manifest, in the pathophysiologic consequences of various insults, in the relative importance of risk factors, and in the responses to several treatments (as reviewed recently). 1,2 Although many of these differences may relate to modifications of the lipid profile, as well as differences in the functions of endothelial and/or vascular smooth muscle cells, it is becoming clear that direct actions within the heart itself must also be considered. The current review will, therefore, focus on sex-specific differences in the remodeling responses of cardiac ventricles to various challenges. Sex-Dependent Differences in Cardiac RemodelingAt baseline, male and female hearts display several differences: (1) coronary artery size is smaller in women 3 ; (2) there are differences in the electrophysiological properties of the hearts, as females have faster resting heart rates and longer rate-corrected QT intervals 4,5 ; (3) male and female hearts differ in terms of the pattern of expression of certain genes 6 ; and (4) there are differences in the contractile properties of male and female hearts. 7,8 More importantly, there are significant differences in the way male and female hearts respond to various challenges. In rodents, aortic bandinginduced pressure overload increases left ventricular mass to the same extent in males and females, but function is better preserved in females, and males show an early transition to heart failure. 9,10 In rats, volume overload induces eccentric dilated hypertrophy in male Sprague-Dawley rats but not in females. 11 Differences in the remodeling responses can also be seen after myocardial infarction (MI), because female rats develop less thickening of noninfarcted regions and less pronounced diastolic dysfunction than their male counterparts, 12 and post-MI rupture of the left ventricle is less frequent in female than in male mice. 13,14 Aging (arguably the most common type of insult on human hearts) may also affect cardiomyocytes in a sex-specific fashion. For instance, various biochemical characteristics (including telomerase activity and several components of the insulin-like growth factor system) vary differently across the lifespan in male and female cardiomyocytes. 15,16 Finally, there are several examples where modification of the cardiac expression of specific genes (either by transgenesis or inactivation) induces cardiac remodeling in male but not in female mice. 17,18 With the exception of longer QT intervals (which increase the risk of "torsades-de-pointe" in females), males generally develop greater remodeling responses than females. 2 The sex-related differences in remodeling of the whole heart are mirrored by differences in intracellular signaling pathways and/or patterns of gene expression. First, rat cardiac myocytes display sexdependent differences in intracellular calcium concentrations under either baseline or stimulated conditions (which is impor...

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Abolition of End-Organ Damage by Antiandrogen Treatment in Female Hypertensive Transgenic Rats

Cited by 50 publications

References 41 publications

Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis

Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis

Estrogen or the AT1 Antagonist Olmesartan Reverses the Development of Profound Hypertension in the Congenic mRen2.Lewis Rat

Hypertensive Cardiac Remodeling in Males and Females

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