PKCδ Mediates Mineralocorticoid Receptor Activation by Angiotensin II to Modulate Smooth Muscle Cell Function.

Angiotensin II (AngII) and the mineralocorticoid receptor (MR) ligand aldosterone both contribute to cardiovascular disorders, including hypertension and adverse vascular remodeling. We previously demonstrated that AngII activates MR-mediated gene transcription in human vascular smooth muscle cells (SMCs), yet the mechanism and the impact on SMC function are unknown. Using an MR-responsive element-driven transcriptional reporter assay, we confirm that AngII induces MR transcriptional activity in vascular SMCs and endothelial cells, but not in Cos1 or human embryonic kidney-293 cells.

No Significant Role for Smooth Muscle Cell Mineralocorticoid Receptors in Atherosclerosis in the Apolipoprotein-E Knockout Mouse Model.

Elevated levels of the hormone aldosterone are associated with increased risk of myocardial infarction and stroke in humans and increased progression and inflammation of atherosclerotic plaques in animal models. Aldosterone acts through the mineralocorticoid receptor (MR) which is expressed in vascular smooth muscle cells (SMCs) where it promotes SMC calcification and chemokine secretion . The objective of this study is to explore the role of the MR specifically in SMCs in the progression of atherosclerosis and the associated vascular inflammation in the apolipoprotein E knockout (ApoE) mouse model.

Effect of Spironolactone on Myocardial Fibrosis and Other Clinical Variables in Patients with Hypertrophic Cardiomyopathy.

Background: Myocardial fibrosis has proved to be an important marker and determinant in the pathogenesis of hypertrophic cardiomyopathy. In particular, scar formation, if substantial, can promote ventricular tachyarrhythmias or progressive heart failure in the absence of left ventricular outflow obstruction. Therefore, an intervention to mitigate myocardial fibrosis would be potentially advantageous to hypertrophic cardiomyopathy patients.

Anti-thrombotic technologies for medical devices.

Thrombosis associated with medical devices may lead to dramatic increases in morbidity, mortality and increased health care costs. Innovative strategies are being developed to reduce this complication and provide a safe biocompatible interface between device and blood. This article aims to describe the biological phenomena underlying device-associated thrombosis, and surveys the literature describing current and developing technologies designed to overcome this challenge.

Circulating multimarker profile of patients with symptomatic heart failure supports enhanced fibrotic degradation and decreased angiogenesis.

Background: Heart failure (HF) involves myocardial fibrosis and dysregulated angiogenesis.

Objective: We explored whether biomarkers of fibrosis and angiogenesis correlate with HF severity.

Methods: Biomarkers of fibrosis [procollagen types I and III (PIP and P3NP), carboxyterminal-telopeptide of type I collagen (ICTP), matrix metalloproteases (MMP2 and MMP9), tissue inhibitor of MMP1 (TIMP1)]; and angiogenesis [placental growth factor (PGF), vascular endothelial growth factor (VEGF), soluble Fms-like tyrosine kinase-1 (sFlt1)] were measured in 52 HF patients and 19 controls.

Mineralocorticoid receptors in vascular disease: connecting molecular pathways to clinical implications.

The mineralocorticoid receptor (MR), a steroid-hormone-activated transcription factor, plays a substantial role in cardiovascular diseases. MR antagonists (MRAs) have long been appreciated as effective treatments for heart failure and hypertension; however, recent research suggests that additional patient populations may also benefit from MRA therapy. Experimental evidence demonstrates that in addition to its classic role in the regulating sodium handling in the kidney, functional MR is expressed in the blood vessels and contributes to hypertension, vascular inflammation and remodeling, and atherogenesis.

Smooth muscle cell mineralocorticoid receptors: role in vascular function and contribution to cardiovascular disease.

The mineralocorticoid receptor (MR), a member of the steroid receptor family, regulates blood pressure by mediating the effects of the hormone aldosterone on renal sodium handling. In recent years, it has become clear that MR is expressed in vascular smooth muscle cells (SMCs), and interest has grown in understanding the direct role of SMC MR in regulating vascular function. This interest stems from multiple clinical studies where MR inhibitor treatment reduced the incidence of cardiovascular events and mortality.

Aldosterone increases early atherosclerosis and promotes plaque inflammation through a placental growth factor-dependent mechanism.

Background: Aldosterone levels correlate with the incidence of myocardial infarction and mortality in cardiovascular patients. Aldosterone promotes atherosclerosis in animal models, but the mechanisms are poorly understood.

Methods And Results: Aldosterone was infused to achieve pathologically relevant levels that did not increase blood pressure in the atherosclerosis-prone apolipoprotein E-knockout mouse (ApoE-/-).

Mineralocorticoid receptor-mediated vascular insulin resistance: an early contributor to diabetes-related vascular disease?

Two-thirds of adults in the U.S. are overweight or obese, and another 26 million have type 2 diabetes (T2D).

Aldosterone regulates vascular gene transcription via oxidative stress-dependent and -independent pathways.

Objective: Aldosterone (Aldo) antagonism prevents cardiovascular mortality by unclear mechanisms. Aldo binds to the mineralocorticoid receptor (MR), a ligand-activated transcription factor, which is expressed in human vascular cells. Here we define the early Aldo-regulated vascular transcriptome and investigate the mechanisms of gene regulation by Aldo in the vasculature that may contribute to vascular disease.

Placental growth factor mediates aldosterone-dependent vascular injury in mice.

In clinical trials, aldosterone antagonists reduce cardiovascular ischemia and mortality by unknown mechanisms. Aldosterone is a steroid hormone that signals through renal mineralocorticoid receptors (MRs) to regulate blood pressure. MRs are expressed and regulate gene transcription in human vascular cells, suggesting that aldosterone might have direct vascular effects.

Molecular basis of TRAP-5'SL RNA interaction in the Bacillus subtilis trp operon transcription attenuation mechanism.

Expression of the Bacillus subtilis trpEDCFBA operon is regulated by the interaction of tryptophan-activated TRAP with 11 (G/U)AG trinucleotide repeats that lie in the leader region of the nascent trp transcript. Bound TRAP prevents folding of an antiterminator structure and favors formation of an overlapping intrinsic terminator hairpin upstream of the trp operon structural genes. A 5'-stem-loop (5'SL) structure that forms just upstream of the triplet repeat region increases the affinity of TRAP-trp RNA interaction, thereby increasing the efficiency of transcription termination.

TRAP-5' stem loop interaction increases the efficiency of transcription termination in the Bacillus subtilis trpEDCFBA operon leader region.

TRAP regulates expression of the Bacillus subtilis trpEDCFBA operon by a transcription attenuation mechanism in which tryptophan-activated TRAP binds to 11 (G/U)AG repeats in the nascent trp leader transcript. Bound TRAP blocks formation of an antiterminator structure and allows formation of an overlapping intrinsic terminator upstream of the trp operon structural genes. A 5' stem-loop (5'SL) structure located upstream of the triplet repeat region also interacts with TRAP.