Prevalence of agonistic autoantibodies against the angiotensin II type 1 receptor and soluble fms-like tyrosine kinase 1 in a gestational age-matched case study.

We showed earlier that activating autoantibodies against the angiotensin II type 1 (AT(1)) receptor (AT1-AA) circulate in preeclamptic women. They may be involved in the pathogenesis of preeclampsia. Protein alignment suggests that the binding site for AT1-AAs is highly homologous to the capsid protein VP2 of parvovirus B19.

Potential relevance of alpha(1)-adrenergic receptor autoantibodies in refractory hypertension.

Background: Agonistic autoantibodies directed at the alpha(1)-adrenergic receptor (alpha(1)-AAB) have been described in patients with hypertension. We implied earlier that alpha(1)-AAB might have a mechanistic role and could represent a therapeutic target.

Methodology/principal Findings: To pursue the issue, we performed clinical and basic studies.

Interaction between P450 eicosanoids and nitric oxide in the control of arterial tone in mice.

Objective: Epoxyeicosatrienoic acids (EETs) serve as endothelial-derived hyperpolarizing factors (EDHF), but may also affect vascular function by other mechanisms. We identified a novel interaction between EETs and endothelial NO release using soluble epoxide hydrolase (sEH) -/- and +/+ mice.

Methods And Results: EDHF responses to acetylcholine in pressurized isolated mesenteric arteries were neither affected by the sEH inhibitor, N-adamantyl-N'-dodecylurea (ADU), nor by sEH gene deletion.

Autoimmunity in kidney diseases.

Renal involvement in autoimmunity has many facets. Glomerular, tubular and vascular structures are targeted and damaged as a consequence of autoimmune processes. Most dramatic and life-threatening causes are observed with diseases that result in rapidly progressive glomerulonephritis (GN), frequently accompanied by involvement of additional non-renal organs.

Novel role for inhibitor of differentiation 2 in the genesis of angiotensin II-induced hypertension.

Background: Angiotensin (Ang) II-induced target-organ damage involves innate and acquired immunity. Mice deficient for the helix-loop-helix transcription factor inhibitor of differentiation (Id2(-/-)) lack Langerhans and splenic CD8a+ dendritic cells, have reduced natural killer cells, and have altered CD8 T-cell memory. We tested the hypothesis that an alteration in the number and quality of circulating blood cells caused by Id2 deletion would ameliorate Ang II-induced target-organ damage.

Neutrophil surface presentation of the anti-neutrophil cytoplasmic antibody-antigen proteinase 3 depends on N-terminal processing.

The neutrophil serine protease proteinase 3 (PR3) is a main autoantigen in anti-neutrophil cytoplasmic antibody-associated vasculitis. PR3 surface presentation on neutrophilic granulocytes, the main effector cells, is pathogenically important. PR3 is presented by the NB1 (CD177) glycoprotein, but how the presentation develops during neutrophil differentiation is not known.

AT1-receptor autoantibodies and uteroplacental RAS in pregnancy and pre-eclampsia.

Pre-eclampsia is a common, pregnancy-induced disorder, consisting of hypertension and proteinuria. The condition is one of the leading causes for maternal and perinatal morbidity and mortality. Nonetheless, the underlying molecular mechanisms remain unclear.

Glucocorticoid-related signaling effects in vascular smooth muscle cells.

Mineralocorticoid receptor blockade protects from angiotensin II-induced target-organ damage. 11beta-Hydroxysteroid dehydrogenase type 2 protects the mineralocorticoid receptor from activation by glucocorticoids; however, high glucocorticoid concentrations and absent 11beta-hydroxysteroid dehydrogenase type 2 in some tissues make glucocorticoids highly relevant mineralocorticoid receptor ligands. We investigated the effects of corticosterone (10(-6) to 10(-12) mol/L) on early vascular mineralocorticoid receptor signaling by Western blotting, confocal microscopy, and myography.

Delayed enhancement cardiac magnetic resonance imaging reveals typical patterns of myocardial injury in patients with various forms of non-ischemic heart disease.

Background: Late gadolinium-hyperenhancement (LHE) on cardiac magnetic resonance imaging (CMR) has been linked to cardiovascular risk in ischemic and non-ischemic heart disease. We aimed to systematically categorize LHE-patterns in a variety of non-ischemic heart diseases (NIHD) and to explore their relationship with left ventricular (LV) function.

Methods: In a retrospective database search, 156 patients with NIHD who exhibited LHE on CMR were identified.

(Pro)renin receptor peptide inhibitor "handle-region" peptide does not affect hypertensive nephrosclerosis in Goldblatt rats.

The (pro)renin receptor [(P)RR], a new component the renin-angiotensin system, was cloned recently. The (P)RR promotes direct mitogen-activated protein kinase signaling and nonproteolytic prorenin activation. We investigated the role of a (P)RR blocker, a peptide consisting of 10 amino acids from the prorenin prosegment called the "handle-region" peptide (HRP), on target organ damage in renovascular hypertensive 2-kidney, 1-clip (2K1C) rats.

Uterine vascular function in a transgenic preeclampsia rat model.

We investigated intrauterine growth restriction, endothelial function, and uterine artery blood flow characteristics in a transgenic preeclampsia rat model with an activated renin-angiotensin system. We compared preeclamptic Sprague-Dawley (SD-PE) rats with normal pregnant Sprague-Dawley and nonpregnant Sprague-Dawley rats. We used transabdominal ultrasound and found that SD-PE rat embryos developed intrauterine growth restriction.

Dietary n-3 polyunsaturated fatty acids and direct renin inhibition improve electrical remodeling in a model of high human renin hypertension.

We compared the effect n-3 polyunsaturated fatty acids (PUFAs) with direct renin inhibition on electrophysiological remodeling in angiotensin II-induced cardiac injury. We treated double-transgenic rats expressing the human renin and angiotensinogen genes (dTGRs) from week 4 to 7 with n-3 PUFA ethyl-esters (Omacor; 25-g/kg diet) or a direct renin inhibitor (aliskiren; 3 mg/kg per day). Sprague-Dawley rats were controls.

Commentary: Shoot the renals!

Atherosclerotic renal artery stenosis (ARAS) is a growing dilemma. The condition is increasingly common and can promulgate hypertension and result in renal failure. However, patients with ARAS generally die owing to their coronaries or cerebral vessels.

Niacin lowers serum phosphate and increases HDL cholesterol in dialysis patients.

Background And Objectives: Adverse effects complicate the use of drugs that are prescribed for phosphate control in dialysis patients. Alternative treatment options are needed.

Design, Setting, Participants, & Measurements: Nicotinic acid inhibits intestinal phosphate reabsorption and increases HDL cholesterol.

Integrated biomarkers in cardiomyopathies: cardiovascular magnetic resonance imaging combined with molecular and immunologic markers--a stepwise approach for diagnosis and treatment.

In an integrated approach, the authors examine the most efficient combination of noninvasive and invasive biochemical, immunologic, functional, molecular, imaging and biopsy-derived biomarkers for their applicability in the diagnosis of cardiomyopathies in general and dilated cardiomyopathy (DCM) in particular. A careful selection out of the cascade of available biomarkers will allow, in individual patients, to diagnose certain conditions of cardiomyopathies without endomyocardial biopsy, e.g.

Dysfunction of dysferlin-deficient hearts.

Mutations in the gene encoding dysferlin cause limb-girdle muscular dystrophy 2B (LGMD2B), a disorder that is believed to spare the heart. We observed dilated cardiomyopathy in two out of seven LGMD2B patients and cardiac abnormalities in three others. Cardiac biopsies showed that dysferlin was completely absent from the sarcolemma and appeared to be trapped within the cardiomyocytes.

Direct renin inhibition with aliskiren in hypertension and target organ damage.

The Joint National Committee and the World Health Organization are in agreement that hypertension in most patients who are treated is controlled inadequately and that rates of cardiovascular morbidity remain high. Additional pharmacologic treatments could ameliorate this situation. The renin-angiotensin-aldosterone system has been a highly successful pharmacologic target, as the system is strongly implicated in the development of hypertension-related target organ damage.

Low-dose renin inhibitor and low-dose AT(1)-receptor blocker therapy ameliorate target-organ damage in rats harbouring human renin and angiotensinogen genes.

We studied the effects of extremely low-dose human renin inhibition (aliskiren) with low angiotensin II receptor blockade (losartan) in a novel double-transgenic rat model harbouring both human renin and angiotensinogen genes. We found that low-dose aliskiren and low-dose losartan effectively reduced mortality and target-organ damage with minimal, non-significant, effects on blood pressure (BP). Our data suggest that renin-angiotensin system (RAS) inhibition ameliorates target-organ damage in an Ang II-driven model of hypertension.

The vasodilator 17,18-epoxyeicosatetraenoic acid targets the pore-forming BK alpha channel subunit in rodents.

17,18-Epoxyeicosatetraenoic acid (17,18-EETeTr) stimulates vascular large-conductance K(+) (BK) channels. BK channels are composed of the pore-forming BK alpha and auxiliary BK beta1 subunits that confer an increased sensitivity for changes in membrane potential and calcium to BK channels. Ryanodine-sensitive calcium-release channels (RyR3) in the sarcoplasmic reticulum (SR) control the process.