Inhibition of Gap Junction Formation Prior to Implantation of Bone Marrow-Derived Mesenchymal Cells Improves Function in the Ischemic Myocardium.

Bone marrow-derived mesenchymal stem cells (BM-MSC) are reported to induce beneficial effects in the heart following ischemia, but a loss of these cells within hours of implantation could significantly diminish their long-term effect. We hypothesized that early coupling between BM-MSC and ischemic cardiomyocytes through gap junctions (GJ) may play an important role in stem cell survival and retention in the acute phase of myocardial ischemia. To determine the effect of GJ inhibition on murine BM-MSC in vivo, we induced ischemia in mice using 90 min left anterior descending coronary artery (LAD) occlusion followed by BM-MSC implantation and reperfusion.

Staying with the trouble of networks.

Networks have risen to prominence as intellectual technologies and graphical representations, not only in science, but also in journalism, activism, policy, and online visual cultures. Inspired by approaches taking trouble as occasion to (re)consider and reflect on otherwise implicit knowledge practices, in this article we explore how problems with network practices can be taken as invitations to attend to the diverse settings and situations in which network graphs and maps are created and used in society. In doing so, we draw on cases from our research, engagement and teaching activities involving making networks, making sense of networks, making networks public, and making network tools.

Low Incidence of Aerodigestive Cancers in Patients With Negative Results From Colonoscopies, Regardless of Findings From Multitarget Stool DNA Tests.

Background & Aims: We aimed to compare the incidence of aerodigestive cancers in persons with negative results from colonoscopies and positive vs negative results from multitarget stool DNA tests for colorectal cancer and vs expected incidence.

Methods: We performed a retrospective cohort study of 1216 subjects with comprehensive patient records and/or cancer registry data from 3 medical centers in North America. Subjects had no neoplasia or only nonadvanced adenomas, based on screening colonoscopy, and either negative results (concordant with colonoscopy, n = 1011) or positive results (discordant colonoscopy, n = 205) from the multitarget stool DNA test.

Asxl2 Mice Exhibit De Novo Cardiomyocyte Production during Adulthood.

Heart attacks affect more than seven million people worldwide each year. A heart attack, or myocardial infarction, may result in the death of a billion cardiomyocytes within hours. The adult mammalian heart does not have an effective mechanism to replace lost cardiomyocytes.

Evidence for Transfer of Membranes from Mesenchymal Stem Cells to HL-1 Cardiac Cells.

This study examined the interaction of mouse bone marrow mesenchymal stem cells (MSC) with cardiac HL-1 cells during coculture by fluorescent dye labeling and then flow cytometry. MSC were layered onto confluent HL-1 cell cultures in a 1 : 4 ratio. MSC gained gap junction permeant calcein from HL-1 cells after 4 hours which was partially reduced by oleamide.

Temporal expression of calcium channel subunits in satellite cells and bone marrow mesenchymal cells.

Bone marrow-derived mesenchymal stem cells (MSC) can be differentiated into myocytes, as well as adipocytes, chondrocytes, and osteocytes in culture. Calcium channels mediate excitation-contraction coupling and are essential for the function of muscle. However, little is known about the expression of calcium channel subunits and calcium handling in stem cells.

PKG-1α leucine zipper domain defect increases pulmonary vascular tone: implications in hypoxic pulmonary hypertension.

Pulmonary hypertension (PH) is a chronic disease characterized by a progressive increase in vasomotor tone, narrowing of the vasculature with structural remodeling, and increase in pulmonary vascular resistance. Current treatment strategies include nitric oxide therapy and methods to increase cGMP-mediated vasodilatation. cGMP-dependent protein kinases (PKG) are known mediators of nitric oxide- and cGMP-induced vasodilatation.

Cardiomyocyte-specific expression of CRNK, the C-terminal domain of PYK2, maintains ventricular function and slows ventricular remodeling in a mouse model of dilated cardiomyopathy.

Up-regulation and activation of PYK2, a member of the FAK family of protein tyrosine kinases, is involved in the pathogenesis of left ventricular (LV) remodeling and heart failure (HF). PYK2 activation can be prevented by CRNK, the C-terminal domain of PYK2. We previously demonstrated that adenoviral-mediated CRNK gene transfer improved survival and LV function, and slowed LV remodeling in a rat model of coronary artery ligation-induced HF.

A cardiac-enriched microRNA, miR-378, blocks cardiac hypertrophy by targeting Ras signaling.

Understanding the regulation of cardiomyocyte growth is crucial for the management of adverse ventricular remodeling and heart failure. MicroRNA-378 (miR-378) is a newly described member of the cardiac-enriched miRNAs, which is expressed only in cardiac myocytes and not in cardiac fibroblasts. We have previously shown that miR-378 regulates cardiac growth during the postnatal period by direct targeting of IGF1R (Knezevic, I.

Mesenchymal stem cells improve cardiac conduction by upregulation of connexin 43 through paracrine signaling.

Mesenchymal stem cells (MSCs) were shown to improve cell survival and alleviate cardiac arrhythmias when transplanted into cardiac tissue; however, little is known about the mechanism by which MSCs modify the electrophysiological properties of cardiac tissue. We aimed to distinguish the influence of cell-cell coupling between myocytes and MSCs from that of MSC-derived paracrine factors on the spontaneous activity and conduction velocity (θ) of multicellular cardiomyocyte preparations. HL-1 cells were plated on microelectrode arrays and their spontaneous activity and θ was determined from field potential recordings.

Maintenance of adult cardiac function requires the chromatin factor Asxl2.

During development and differentiation, cell type-specific chromatin configurations are set up to facilitate cell type-specific gene expression. Defects in the establishment or the maintenance of the correct chromatin configuration have been associated with diseases ranging from leukemia to muscular dystrophy. The heart expresses many chromatin factors, and we are only beginning to understand their roles in heart development and function.

Cardiovascular responses and differential changes in mitogen-activated protein kinases following repeated episodes of binge drinking.

Aims: Excessive alcohol use in the form of binge drinking is associated with many adverse medical outcomes. Using an animal model, the primary objective of this study was to determine the effects of repeated episodes of binge drinking on myocardial structure, blood pressure (BP) and activation of mitogen-activated protein kinases (MAPKs). The effects of carvedilol, a beta-adrenergic blocker, were also examined in this animal model of binge drinking.

Induction of cardiac myogenic lineage development differs between mesenchymal and satellite cells and is accelerated by bone morphogenetic protein-4.

Our aim was to further elucidate the cardiac lineage development of bone marrow-derived mesenchymal stem cells (MSC) and to identify cells which had the potential for cardiac myogenic differentiation when compared to skeletal muscle satellite (Sk-sat) myogenesis. Unlike Sk-sat, MSC expressed the early cardiac markers Nkx2.5 and GATA4.

Phosphoprotein abundance changes in hypertensive cardiac remodeling.

There is over-whelming evidence that protein phosphorylations regulate cardiac function and remodeling. A wide variety of protein kinases, e.g.

Protein kinase G-I deficiency induces pulmonary hypertension through Rho A/Rho kinase activation.

Protein kinase G (PKG) plays an important role in the regulation of vascular smooth cell contractility and is a critical mediator of nitric oxide signaling, which regulates cardiovascular homeostasis. PKG-I-knockout (Prkg1(-/-)) mice exhibit impaired nitric oxide/cGMP-dependent vasorelaxation and systemic hypertension. However, it remains unknown whether PKG-I deficiency induces pulmonary hypertension.

Mesenchymal stem cells secrete multiple cytokines that promote angiogenesis and have contrasting effects on chemotaxis and apoptosis.

We have previously shown that mesenchymal stem cells (MSC) improve function upon integration in ischemic myocardium. We examined whether specific cytokines and growth factors produced by MSCs are able to affect angiogenesis, cellular migration and apoptosis. Conditioned media (CM) was prepared by culturing MSC for 48 hours.

Excitation-contraction coupling in ventricular myocytes is enhanced by paracrine signaling from mesenchymal stem cells.

In clinical trials mesenchymal stem cells (MSCs) are transplanted into cardiac ischemic regions to decrease infarct size and improve contractility. However, the mechanism and time course of MSC-mediated cardioprotection are incompletely understood. We tested the hypothesis that paracrine signaling by MSCs promotes changes in cardiac excitation-contraction (EC) coupling that protects myocytes from cell death and enhances contractility.

Cardiac-specific expression of the tetracycline transactivator confers increased heart function and survival following ischemia reperfusion injury.

Mice expressing the tetracycline transactivator (tTA) transcription factor driven by the rat α-myosin heavy chain promoter (α-MHC-tTA) are widely used to dissect the molecular mechanisms involved in cardiac development and disease. However, these α-MHC-tTA mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury in both in vitro and in vivo models in the absence of associated cardiac hypertrophy or remodeling. Cardiac function, as assessed by echocardiography, did not differ between α-MHC-tTA and control animals, and there were no noticeable differences observed between the two groups in HW/TL ratio or LV end-diastolic and end-systolic dimensions.

Myocardial infarction in mice alters sarcomeric function via post-translational protein modification.

Myocardial physiology in the aftermath of myocardial infarction (MI) before remodeling is an under-explored area of investigation. Here, we describe the effects of MI on the cardiac sarcomere with focus on the possible contributions of reactive oxygen species. We surgically induced MI in 6-7-month-old female CD1 mice by ligation of the left anterior descending coronary artery.

Interventricular differences in myofilament function in experimental congestive heart failure.

This study was conducted to identify molecular mechanisms which explain interventricular differences in myofilament function in experimental congestive heart failure (CHF). CHF was induced in rats by chronic aortic banding or myocardial infarction for 32-36 weeks. Right and left ventricular (RV, LV) myocytes were mechanically isolated, triton-skinned, and attached to a force transducer and motor arm.

Myofilament calcium sensitization delays decompensated hypertrophy differently between the sexes following myocardial infarction.

Contractile dysfunction is common to many forms of cardiovascular disease. Approaches directed at enhancing cardiac contractility at the level of the myofilaments during heart failure (HF) may provide a means to improve overall cardiovascular function. We are interested in gender-based differences in cardiac function and the effect of sarcomere activation agents that increase contractility.

Sub-proteomic fractionation, iTRAQ, and OFFGEL-LC-MS/MS approaches to cardiac proteomics.

Using an in solution based approach with a sub-proteomic fraction enriched in cardiac sarcomeric proteins; we identified protein abundance in ischemic and non-ischemic regions of rat hearts stressed by acute myocardial ischemia by ligating the left-anterior descending coronary artery in vivo for 1h without reperfusion. Sub-cellular fractionation permitted more in depth analysis of the proteome by reducing the sample complexity. A series of differential centrifugations produced nuclear, mitochondrial, cytoplasmic, microsomal, and sarcomeric enriched fractions of ischemic and non-ischemic tissues.

Delayed enrichment of mesenchymal cells promotes cardiac lineage and calcium transient development.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) can be induced to differentiate into myogenic cells. Despite their potential, previous studies have not been successful in producing a high percentage of cardiac-like cells with a muscle phenotype. We hypothesized that cardiac lineage development in BM-MSC is related to cell passage, culture milieu, and enrichment for specific cell subtypes before and during differentiation.

Ablation of iNOS delays cardiac contractile dysfunction in chronic hypertension.

We investigated the role of inducible NOS (iNOS) on cardiac function during the development of left ventricular hypertrophy. Hypertrophy was induced by pressure-overload via short-term (2.5 months) or long-term (6.