Background: Arterial hypertension and its organ sequelae show characteristics of T cell–mediated inflammatory diseases. Experimental anti-inflammatory therapies have been shown to ameliorate hypertensive end-organ damage. Recently, the CANTOS study (Canakinumab Antiinflammatory Thrombosis Outcome Study) targeting interleukin-1β demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays a pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFAs) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in 2 different mouse models of hypertensive cardiovascular damage. Methods: To investigate the effect of SCFAs on hypertensive cardiac damage and atherosclerosis, wild-type NMRI or apolipoprotein E knockout–deficient mice received propionate (200 mmol/L) or control in the drinking water. To induce hypertension, wild-type NMRI mice were infused with angiotensin II (1.44 mg·kg ^–1 ·d ^–1 subcutaneous) for 14 days. To accelerate the development of atherosclerosis, apolipoprotein E knockout mice were infused with angiotensin II (0.72 mg·kg ^–1 ·d ^–1 subcutaneous) for 28 days. Cardiac damage and atherosclerosis were assessed using histology, echocardiography, in vivo electrophysiology, immunofluorescence, and flow cytometry. Blood pressure was measured by radiotelemetry. Regulatory T cell depletion using PC61 antibody was used to examine the mode of action of propionate. Results: Propionate significantly attenuated cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in both models. Susceptibility to cardiac ventricular arrhythmias was significantly reduced in propionate-treated angiotensin II–infused wild-type NMRI mice. Aortic atherosclerotic lesion area was significantly decreased in propionate-treated apolipoprotein E knockout–deficient mice. Systemic inflammation was mitigated by propionate treatment, quantified as a reduction in splenic effector memory T cell frequencies and splenic T helper 17 cells in both models, and a decrease in local cardiac immune cell infiltration in wild-type NMRI mice. Cardioprotective effects of propionate were abrogated in regulatory T cell–depleted angiotensin II–infused mice, suggesting the effect is regulatory T cell–dependent. Conclusions: Our data emphasize an immune-modulatory role of SCFAs and their importance for cardiovascular health. The data suggest that lifestyle modifications leading to augmented SCFA production could be a beneficial nonpharmacological preventive strategy for patients with hypertensive cardiovascular disease.

The mineralocorticoid aldosterone increases in plasma in healthy pregnancy along with renin and angiotensin II and plays a key role in the physiological plasma volume expansion. In mice, aldosterone contributes to an optimal fetal development by enhancing PlGF (placental growth factor) expression and trophoblast cell proliferation. In preeclampsia, there is coincident suppression of aldosterone and impaired placental development. We hypothesized that aldosterone independently contributes to placental and birth weight in humans, and high dietary sodium and low potassium intakes affect this relationship adversely. We analyzed 24-hour urine collections and plasma samples from gestational week 29 in a subsample of 569 pregnant women from the Odense Child Cohort—a Danish population-based longitudinal cohort study. Plasma and urinary aldosterone were measured by ELISA, sodium and potassium excretions by flame photometer. Predictive values of aldosterone levels and sodium and potassium intakes were assessed by multiple and Cox regression analyses. Primary outcomes were placental weight and birth weight. Secondary outcome was preeclampsia. Urinary aldosterone excretion at gestational week 29 independently contributed to placental and birth weights (adjusted β-coefficients [95% CI], 24.50 [9.66–39.35] and 9.59 [4.57–14.61], respectively). Aldosterone levels were not associated to preeclampsia incidence. Salt intake >6 g/d was associated with development of preeclampsia (hazard ratio [95% CI], 5.68 [1.51–21.36]). At gestational week 29, urinary aldosterone excretion is an independent predictor of placental and birth weights. High salt intake is a risk factor for preeclampsia. In perspective, suppression of aldosterone in pregnancy has adverse trophic effects.

Heart failure with preserved ejection fraction (HFpEF) can arise from cardiac and vascular remodeling processes following long-lasting hypertension. Efficacy of common HF therapeutics is unsatisfactory in HFpEF. Evidence suggests that stimulators of the nitric oxide–sensitive soluble guanylyl cyclase (NOsGC) could be of use here. We aimed to characterize the complex cardiovascular effects of NOsGC stimulation using NO-independent stimulator BAY 41-8543 in a double-transgenic rat (dTGR) model of HFpEF. We show a drastically improved survival rate of treated dTGR. We observed less cardiac fibrosis, macrophage infiltration, and gap junction remodeling in treated dTGR. Microarray analysis revealed that treatment of dTGR corrected the dysregulateion of cardiac genes associated with fibrosis, inflammation, apoptosis, oxidative stress, and ion channel function toward an expression profile similar to healthy controls. Treatment reduced systemic blood pressure levels and improved endothelium-dependent vasorelaxation of resistance vessels. Further comprehensive in vivo phenotyping showed an improved diastolic cardiac function, improved hemodynamics, and less susceptibility to ventricular arrhythmias. Short-term BAY 41-8543 application in isolated untreated transgenic hearts with structural remodeling significantly reduced the occurrence of ventricular arrhythmias, suggesting a direct nongenomic role of NOsGC stimulation on excitation. Thus, NOsGC stimulation was highly effective in improving several HFpEF facets in this animal model, underscoring its potential value for patients.

Preeclampsia is associated with increased cardiovascular long-term risk; however, the underlying functional and structural mechanisms are unknown. We investigated maternal cardiac alterations after preeclampsia. Female rats harboring the human angiotensinogen gene [TGR(hAogen)L1623] develop a preeclamptic phenotype with hypertension and albuminuria during pregnancy when mated with male rats bearing the human renin gene [TGR(hRen)L10J] but behave physiologically normal before and after pregnancy. Furthermore, rats were treated with pravastatin. We tested the hypothesis that statins are a potential therapeutic intervention to reduce cardiovascular alterations due to simulated preeclamptic pregnancy. Although hypertension persists for only 8 days in pregnancy, former preeclampsia rats exhibit significant cardiac hypertrophy 28 days after pregnancy observed in both speckle tracking echocardiography and histological staining. In addition, fibrosis and capillary rarefaction was evident. Pravastatin treatment ameliorated the remodeling and improved cardiac output postpartum. Preeclamptic pregnancy induces irreversible structural changes of cardiac hypertrophy and fibrosis, which can be moderated by pravastatin treatment. This pathological cardiac remodeling might be involved in increased cardiovascular risk in later life.

Diabetic pregnancy is correlated with increased risk of metabolic and neurological disorders in the offspring putatively mediated epigenetically. Little is known about epigenetic changes already present in fetuses of diabetic pregnancies. We aimed at characterizing the perinatal environment after preexisting maternal diabetes mellitus and at identifying relevant epigenetic changes in the fetus. We focused on the transcription factor Srebf2 (sterol regulatory element binding transcription factor 2), a master gene in regulation of cholesterol metabolism. We tested whether diabetic pregnancy induces epigenetic changes in the Srebf2 promoter and if they become manifest in altered Srebf2 gene expression. We worked with a transgenic rat model of type 2 diabetes mellitus (Tet29) in which the insulin receptor is knocked down by doxycycline-induced RNA interference. Doxycycline was administered preconceptionally to Tet29 and wild-type control rats. Only Tet29 doxycycline dams were hyperglycemic, hyperinsulinemic, and hyperlipidemic. Gene expression was analyzed with quantitative real-time reverse transcriptase polymerase chain reaction and CpG promoter methylation with pyrosequencing. Immunohistochemistry was performed on fetal brains. Fetuses from diabetic Tet29 dams were hyperglycemic and growth restricted at the end of pregnancy. They further displayed decreased liver and brain weight with concomitant decreased microglial activation in the hippocampus in comparison to fetuses of normoglycemic mothers. Importantly, diabetic pregnancy induced CpG hypermethylation of the Srebf2 promoter in the fetal liver and brain, which was associated with decreased Srebf2 gene expression. In conclusion, diabetic and hyperlipidemic pregnancy induces neurological, metabolic, and epigenetic alterations in the rat fetus. Srebf2 is a potential candidate mediating intrauterine environment-driven epigenetic changes and later diabetic offspring health.