Small Interfering RNA Therapy for the Management and Prevention of Hypertension.

Purpose Of Review: To review currently existing knowledge on a new type of antihypertensive treatment, small interfering RNA (siRNA) targeting hepatic angiotensinogen.

Recent Findings: Targeting angiotensinogen synthesis in the liver with siRNA allows reaching a suppression of renin-angiotensin system (RAS) activity for up to 6 months after 1 injection. This might revolutionize antihypertensive treatment, as it could overcome non-adherence, the major reason for inadequate blood pressure control.

Glycosylated fibronectin as a biomarker for preeclampsia and preeclampsia-related complications.

Objectives: To evaluate glycosylated fibronectin (GlyFn) as a novel biomarker for preeclampsia and preeclampsia-related complications, and to compare GlyFn to traditional biomarkers, including soluble Fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF).

Study Design: Secondary analysis of a prospective cohort study (n = 524) with suspected preeclampsia (control), gestational hypertension (GH), or confirmed preeclampsia/hemolysis, elevated liver enzymes and low platelets syndrome (PE/HELLP).

Main Outcome Measures: GlyFn levels in PE/HELLP versus control and GH.

Innovative hypertension treatments: Transitioning from conventional therapies to siRNA-based solutions.

Hypertension remains a critical global health issue, despite significant advancements in treatment, management and preventive approaches. Current antihypertensive drugs have limitations, such as low adherence, renin-angiotensin-aldosterone system reactivation, and drug resistance,. Ongoing preclinical and clinical studies for siRNA therapies show promising results, demonstrating significant blood pressure reductions and their potential as effective, durable treatments.

The Extracellular Matrix and Cardiac Pressure Overload: Focus on Novel Treatment Targets.

Heart failure is a significant health issue in developed countries, often stemming from conditions like hypertension, which imposes a pressure overload on the heart. Despite various treatment strategies for heart failure, many lack long-term effectiveness. A critical aspect of cardiac disease is the remodeling of the heart, where compensatory changes in the extracellular matrix exacerbate disease progression.

5/6 Nephrectomy impairs acute kaliuretic responses and predisposes to postprandial hyperkalemia.

The susceptibility of patients with chronic kidney disease to develop postprandial hyperkalemia suggests alterations in normal kidney sodium (Na) and potassium (K) handling, but the exact nature of these changes is largely unknown. To address this, we analyzed the natriuretic and kaliuretic responses to diuretics and acute K loading in rats who underwent 5/6 nephrectomy (5/6Nx) and compared this with the response in sham-operated rats. The natriuretic and kaliuretic responses to furosemide, hydrochlorothiazide, and amiloride were largely similar between 5/6Nx and sham rats except for a significantly reduced kaliuretic response to hydrochlorothiazide in 5/6Nx rats.

Differential expression of components of the CGRP-receptor family in human coronary and human middle meningeal arteries: functional implications.

Background: Different responses in human coronary arteries (HCA) and human middle meningeal arteries (HMMA) were observed for some of the novel CGRP receptor antagonists, the gepants, for inhibiting CGRP-induced relaxation. These differences could be explained by the presence of different receptor populations in the two vascular beds. Here, we aim to elucidate which receptors are involved in the relaxation to calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2) in HCA and HMMA.

Statins, but not proprotein convertase subtilisin-kexin type 9 inhibitors, lower chemerin in hypercholesterolemia via low-density lipoprotein receptor upregulation.

Hypercholesterolemia is characterized by elevated low-density lipoprotein (LDL)-cholesterol levels and an increased risk of cardiovascular disease. The adipokine chemerin is an additional risk factor. Here we investigated whether cholesterol-lowering with statins or proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) affects chemerin.

Maternal serum PlGF associates with 3D power doppler ultrasound markers of utero-placental vascular development in the first trimester: the rotterdam periconception cohort.

Objective (s): Circulating angiogenic factors are used for prediction of placenta-related complications, but their associations with first-trimester placental development is unknown. This study investigates associations between maternal angiogenic factors and utero-placental vascular volume (uPVV) and utero-placental vascular skeleton (uPVS) as novel imaging markers of volumetric and morphologic (branching) development of the first-trimester utero-placental vasculature.

Methods: In 185 ongoing pregnancies from the VIRTUAL Placenta study, a subcohort of the ongoing prospective Rotterdam Periconception cohort, three-dimensional power Doppler ultrasounds of the placenta were obtained at 7-9-11 weeks gestational age (GA).

Sex differences in CGRP-induced vasodilation of human middle meningeal arteries but not human coronary arteries: implications for migraine.

Background: Migraine prevalence and levels of calcitonin gene-related peptide (CGRP), a peptide involved in migraine pathophysiology, differ between men and women, and appear to be affected by changes in sex hormones. The present study investigated the sex-specific responses to CGRP in human isolated arteries.

Methods: CGRP-induced relaxation of 62 (28 men and 34 women) human isolated middle meningeal arteries (HMMA) and 139 (69 men and 70 women) human isolated coronary arteries (HCA) was compared between men and women in groups <50 years and ≥50 years of age as a proxy for pre- and postmenopausal status in women, as well as matched-age groups for men.

Effects of Oral Butyrate on Blood Pressure in Patients With Hypertension: A Randomized, Placebo-Controlled Trial.

Background: The microbiota-derived short chain fatty acid butyrate has been shown to lower blood pressure (BP) in rodent studies. Nonetheless, the net effect of butyrate on hypertension in humans remains uncovered. In this study, for the first time, we aimed to determine the effect of oral butyrate on BP in patients with hypertension.

Calcineurin inhibitor effects on kidney electrolyte handling and blood pressure: tacrolimus versus voclosporin.

Background: Calcineurin inhibitors (CNIs) affect kidney electrolyte handling and blood pressure (BP) through an effect on the distal tubule. The second-generation CNI voclosporin causes hypomagnesaemia and hypercalciuria less often than tacrolimus. This suggests different effects on the distal tubule, but this has not yet been investigated experimentally.

Short-Lived Active Prorenin: Precursor of So-Called Native Prorenin.

The enzymatic activity of the aspartic protease, renin, is critical for its function in blood pressure regulation and sodium homeostasis. Incubation of so-called native prorenin at low pH leads to its activation. After binding to transition-state mimicking renin inhibitors at neutral pH, prorenin attains the active conformation, as indicated by immunosorbent assay using monoclonal antibodies specific for epitopes of the prosegment or the renin body.

Investigation of Strategies to Block Downstream Effectors of AT1R-Mediated Signalling to Prevent Aneurysm Formation in Marfan Syndrome.

Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation.

Angiotensin-(1-12): Does It Exist? A Critical Evaluation in Humans, Rats, and Mice.

Background: Angiotensin-(1-12), measured by a self-developed, polyclonal antibody-based radioimmunoassay, has been suggested to act as an alternative precursor of angiotensin II. A more reliable detection method would be liquid chromatography-tandem mass spectrometry.

Methods: We set up the quantification of human and murine angiotensin-(1-12) by liquid chromatography-tandem mass spectrometry and then used this method to measure angiotensin-(1-12) in human, rat, and mouse blood samples, as well as in mouse brain, mouse kidney, and rat heart.

Counteracting Angiotensinogen Small-Interfering RNA-Mediated Antihypertensive Effects With REVERSIR.

Background: Small-interfering RNA (siRNA) targeting hepatic AGT (angiotensinogen) mRNA depletes AGT, lowering blood pressure for up to 6 months. However, certain situations may require a rapid angiotensin increase. The REVERSIR (RVR) - reverse siRNA silencing technology a potential approach to counteract siRNA effects.

Vacuolar H-ATPase in Diabetes, Hypertension, and Atherosclerosis.

Vacuolar H-ATPase (V-ATPase) is a multisubunit protein complex which, along with its accessory proteins, resides in almost every eukaryotic cell. It acts as a proton pump and as such is responsible for regulating pH in lysosomes, endosomes, and the extracellular space. Moreover, V-ATPase has been implicated in receptor-mediated signaling.