Blocking of frizzled signaling with a homologous peptide fragment of wnt3a/wnt5a reduces infarct expansion and prevents the development of heart failure after myocardial infarction.

Background: The molecular pathways that control the wound healing after myocardial infarction (MI) are not completely elucidated. One of these pathways is the Wnt/Frizzled pathway. In this study, we evaluated Frizzled as a novel therapeutic target for MI.

Application of a ligand-based theoretical approach to derive conversion paths and ligand conformations in CYP11B2-mediated aldosterone formation.

The biosynthesis of the mineralocorticoid hormone aldosterone involves a multistep hydroxylation of 11-deoxycorticosterone at the 11- and 18-positions, resulting in the formation of corticosterone and 18-hydroxycorticosterone, the final precursor of aldosterone. Two members of the cytochrome P450 11B family, CYP11B1 and CYP11B2, are known to catalyze these 11- and 18-hydroxylations, however, only CYP11B2 can oxidize 18-hydroxycorticosterone to aldosterone. It is unknown what sequence of hydroxylations leads to the formation of 18-hydroxycorticosterone.

Inhibition of Wnt/β-catenin signaling by p38 MAP kinase inhibitors is explained by cross-reactivity with casein kinase Iδ/ɛ.

Wnt/β-catenin signaling plays essential roles in embryonic development, adult stem cell maintenance, and disease. Screening of a small molecule compound library with a β-galactosidase fragment complementation assay measuring β-catenin nuclear entry revealed TAK-715 and AMG-548 as inhibitors of Wnt-3a-stimulated β-catenin signaling. TAK-715 and AMG-548 are inhibitors of p38 mitogen-activated protein kinase, which has been suggested to regulate activation of Wnt/β-catenin signaling.

Urinary nitric oxide metabolites and individual blood pressure progression to overt hypertension.

Baseline blood pressure (BP) is the strongest known determinant of progression to hypertension, but for an individualized prediction of the incidence of hypertension, the identification of additional biomarkers is crucial. In animal models of hypertension, renal nitric oxide (NO) handling modifies the systemic BP responses prior to the development of hypertension. This study aimed to evaluate whether urinary NO metabolites (NOx) predict the progression of hypertension in normotensive subjects.

Wnt/frizzled signalling modulates the migration and differentiation of immortalized cardiac fibroblasts.

Aims: The Wnt/frizzled (Fzd) signal transduction cascade has been implicated in the proliferation, differentiation, and migration of many cell types, but the role of this pathway in cardiac fibroblast differentiation is not known. Our lab previously showed an up-regulation of Fzd-1 and -2 expression in myofibroblasts after myocardial infarction (MI), indicating a potential role for the Fzd receptor in fibroblast-myofibroblast differentiation. The present study was performed to further define the role of specific Wnt and Fzd proteins in the proliferation, migration, and differentiation of cardiac fibroblasts.

Synthesis, biological evaluation, and molecular modeling of 1-benzyl-1H-imidazoles as selective inhibitors of aldosterone synthase (CYP11B2).

Reducing aldosterone action is beneficial in various major diseases such as heart failure. Currently, this is achieved with mineralocorticoid receptor antagonists, however, aldosterone synthase (CYP11B2) inhibitors may offer a promising alternative. In this study, we used three-dimensional modeling of CYP11B2 to model the binding modes of the natural substrate 18-hydroxycorticosterone and the recently published CYP11B2 inhibitor R-fadrozole as a rational guide to design 44 structurally simple and achiral 1-benzyl-1H-imidazoles.

beta-Galactosidase enzyme fragment complementation for the measurement of Wnt/beta-catenin signaling.

Wnt/beta-catenin signaling is an important regulator of cell polarity, proliferation, and stem cell maintenance during development and adulthood. Wnt proteins induce the nuclear accumulation of beta-catenin, which regulates the expression of Wnt-responsive genes through association with TCF/LEF transcription factors. Aberrant Wnt/beta-catenin signaling has been implicated in a plethora of pathologies and, most notably, underlies initiation and expansion of several cancers.

Mouse strain determines the outcome of wound healing after myocardial infarction.

Aims: Our objective was to study the effect of the genetic background on the wound healing process after myocardial infarction (MI) in mice.

Methods And Results: MI was induced in five different mouse strains (BalbC, C57Bl6, FVB, 129S6, and Swiss). At 3, 14, and 28 days after MI, cardiac dimensions were monitored by echocardiography and histology, whereas cardiac function was determined by direct intraventricular pressure measurements (dP/dt).

Molecular imaging for efficacy of pharmacologic intervention in myocardial remodeling.

Objectives: Using molecular imaging techniques, we examined interstitial alterations during postmyocardial infarction (MI) remodeling and assessed the efficacy of antiangiotensin and antimineralocorticoid intervention, alone and in combination.

Background: The antagonists of the renin-angiotensin-aldosterone axis restrict myocardial fibrosis and cardiac remodeling after MI and contribute to improved survival. Radionuclide imaging with technetium-99m-labeled Cy5.

Effects of intrapericardial sotalol and flecainide on transmural atrial electrophysiology and atrial fibrillation.

Introduction: Intrapericardial (IPC) delivery of antiarrhythmic agents is an appealing idea to increase the therapeutic width and reduce side effects of drugs, particularly in the thin atria. The aim of this study was to determine the effects of IPC versus intravenous (IV) d,l-sotalol and flecainide infusion on transmural atrial electrophysiology and sustained atrial fibrillation (AF) in the goat.

Methods And Results: Effects of IPC and IV sotalol and flecainide infusion on epi- and endocardial atrial electrophysiology, ECG, and tissue drug concentrations were studied in goats without and with persistent AF (>24 hours).

Molecular imaging of interstitial alterations in remodeling myocardium after myocardial infarction.

Objectives: The purpose of this study was to evaluate interstitial alterations in myocardial remodeling using a radiolabeled Cy5.5-RGD imaging peptide (CRIP) that targets myofibroblasts.

Background: Collagen deposition and interstitial fibrosis contribute to cardiac remodeling and heart failure after myocardial infarction (MI).

Comparison of the effects of intrapericardial and intravenous aldosterone infusions on left ventricular fibrosis in rats.

Background: Aldosterone plays a detrimental role in the pathology of chronic heart failure. An important mechanism resides in its ability to evoke extensive fibrosis in the heart. However, the locations of the aldosterone interaction sites responsible for triggering cardiac fibrosis are puzzling.

Stably overexpressed human Frizzled-2 signals through the beta-catenin pathway and does not activate Ca2+-mobilization in Human Embryonic Kidney 293 cells.

Signal transduction via the Frizzled family of seven-transmembrane receptors controls important developmental processes. Aberrant signaling caused by altered Frizzled receptor activity or by mutations in downstream signaling components has been implicated in several adult pathologies. A diverse array of intracellular signaling pathways has been suggested to transduce the signals exerted in cells when secreted ligands of the Wnt family bind to Frizzled receptors.

G protein-independent cell-based assays for drug discovery on seven-transmembrane receptors.

Conventional cell-based assays for seven-transmembrane receptors, also known as G protein-coupled receptors, rely on the coupling of the ligand-bound receptor to heterotrimeric G proteins. New assay methods have become available that are not based on G protein activation, but that apply the molecular mechanism underlying the attenuation of G protein signaling mediated by beta-arrestin. beta-arrestin is a cytoplasmic protein that targets receptors to clathrin-coated endocytotic vesicles for degradation or recycling.

Defective intercellular adhesion complex in myocardium predisposes to infarct rupture in humans.

Objectives: Our goal was to evaluate intercellular adhesion complex proteins in myocardium in human infarct rupture.

Background: Infarct rupture, a fatal complication of myocardial infarction (MI), has been attributed to a defective cell adhesion complex in a transgenic mouse model.

Methods: Heart samples were collected from autopsies from infarct rupture and control (nonrupture) MI patients.

The Wnt/frizzled pathway in cardiovascular development and disease: friend or foe?

Proteins from the Wnt family have been implicated in cell-cell communication in a wide variety of developmental and physiological processes. Wnt signaling is required for different aspects of cardiac and vascular development, including myocardial specification, cardiac morphogenesis and cardiac valve formation as well as endothelial and vascular smooth muscle cell proliferation. Defective Wnt signaling can result in different cardiac and vascular abnormalities.

Increased matrix metalloproteinase-8 and -9 activity in patients with infarct rupture after myocardial infarction.

Background: Infarct rupture is a usually fatal complication of myocardial infarction (MI), for which no molecular mechanism has been described in humans. Experimental evidence in mouse models suggests that the degradation of the extracellular matrix by matrix metalloproteinases (MMPs) plays an important role in infarct rupture. The present study was designed to study the role of MMP-2, MMP-8, and MMP-9 in human infarct rupture.

The Wnt/frizzled/GSK-3 beta pathway: a novel therapeutic target for cardiac hypertrophy.

An excessive hypertrophic response of the heart to an increased workload is a leading cause of heart failure. At present, cardiac hypertrophy is treated with inhibitors of the renin-angiotensin system or with beta-adrenoceptor antagonists. These current therapeutic strategies inhibit prohypertrophic signaling pathways, but this therapy is inadequate in a substantial number of patients.

Sustained tubulo-interstitial protection in SHRs by transient losartan treatment: an effect of decelerated aging?

Background: Hypertensive target organ damage shows characteristics of accelerated cell turnover and aging. This might have developed during the evolution of hypertension. In the kidney, high cell turnover is mainly restricted to tubular cells.

Prehypertensive renin-angiotensin-aldosterone system blockade in spontaneously hypertensive rats ameliorates the loss of long-term vascular function.

Arterial function after long-term hypertension is characterized by remodeling, endothelial dysfunction and reduction of previously enhanced contractile responses. We investigated whether transient prehypertensive renin-angiotensin-aldosterone system (RAAS) blockade modifies long-term arterial function. Wistar Kyoto rats (WKY) (i) and spontaneously hypertensive rats (SHR) (ii) were prehypertensively (week 4-8) treated with losartan (iii) or spironolactone (iv) (20 and 0.

Transient prehypertensive treatment in spontaneously hypertensive rats: a comparison of spironolactone and losartan regarding long-term blood pressure and target organ damage.

Objective: We previously demonstrated that when the renin-angiotensin system (RAS) is transiently blocked by an angiotensin receptor blocker (ARB) in young spontaneously hypertensive rats (SHR), this results in a prolonged blood pressure decrease and protection against target organ damage. Aldosterone is an essential hormone in the RAS, and contributes to pathologic remodeling. Thus, part of the protective effects of the ARB may be due to inhibition of aldosterone-mediated effects.

Fadrozole reverses cardiac fibrosis in spontaneously hypertensive heart failure rats: discordant enantioselectivity versus reduction of plasma aldosterone.

Reversal of cardiac fibrosis is a major determinant of the salutary effects of mineralocorticoid receptor antagonists in heart failure. Recently, R-fadrozole was coined as an aldosterone biosynthesis inhibitor, offering an appealing alternative to mineralocorticoid receptor antagonists to block aldosterone action. The present study aimed to evaluate the effects of R- and S-fadrozole on plasma aldosterone and urinary aldosterone excretion rate and to compare their effectiveness vs.

Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics.

Aldosterone is synthesised by aldosterone synthase (CYP11B2). CYP11B2 has a highly homologous isoform, steroid 11beta-hydroxylase (CYP11B1), which is responsible for the biosynthesis of aldosterone precursors and glucocorticoids. To investigate aldosterone biosynthesis and facilitate the search for selective CYP11B2 inhibitors, we constructed three-dimensional models for CYP11B1 and CYP11B2 for both human and rat.

Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophy.

The hypertrophic response of the heart has been recognized recently as the net result of activation of prohypertrophic and antihypertrophic pathways. Here we report the involvement of the Wnt/Frizzled pathway in the onset of cardiac hypertrophy development. Stimulation of the Wnt/Frizzled pathway activates the disheveled (Dvl) protein.

Transient AT1 receptor-inhibition in prehypertensive spontaneously hypertensive rats results in maintained cardiac protection until advanced age.

Objective: In young spontaneously hypertensive rats (SHR), transient angiotensin II type 1 receptor (AT1R) blockade decreases blood pressure for a prolonged period. We tested the hypothesis that transient AT1R blockade in SHR leads to cardiac protection until advanced age.

Method: Wistar-Kyoto rats, SHR and transiently losartan-treated SHR (SHR-Los) (20 mg/kg per day; weeks 4-8 of age) were followed up until week 72 (n=9 each group), including repeated echocardiography, radiotelemetric investigations and 24-h urine collection.