Systemic AAV9.LAMP2B injection reverses metabolic and physiologic multiorgan dysfunction in a murine model of Danon disease.

Danon disease (DD) is a rare X-linked autophagic vacuolar myopathy associated with multiorgan dysfunction, including the heart, skeletal muscle, and liver. There are no specific treatments, and most male patients die from advanced heart failure during the second or third decade of life. DD is caused by mutations in the lysosomal-associated membrane protein 2 () gene, a key mediator of autophagy.

Talin and Kindlin as Integrin-Activating Proteins: Focus on the Heart.

Integrin receptors enable cells to sense and respond to their chemical and physical environment. As a class of membrane receptors, they provide a dynamic, tightly regulated link between the extracellular matrix or cellular counter-receptors and intracellular cytoskeletal and signaling networks. They enable transmission of mechanical force across the plasma membrane, and particularly for cardiomyocytes, may sense the mechanical load placed on cells.

Combinatorial interactions of genetic variants in human cardiomyopathy.

Dilated cardiomyopathy (DCM) is a leading cause of morbidity and mortality worldwide; yet how genetic variation and environmental factors impact DCM heritability remains unclear. Here, we report that compound genetic interactions between DNA sequence variants contribute to the complex heritability of DCM. By using genetic data from a large family with a history of DCM, we discovered that heterozygous sequence variants in the () and () genes cose-gregate in individuals affected by DCM.

Analyzing Oxygen Consumption Rate in Primary Cultured Mouse Neonatal Cardiomyocytes Using an Extracellular Flux Analyzer.

Mitochondria and oxidative metabolism are critical for maintaining cardiac muscle function. Research has shown that mitochondrial dysfunction is an important contributing factor to impaired cardiac function found in heart failure. By contrast, restoring defective mitochondrial function may have beneficial effects to improve cardiac function in the failing heart.

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy.

Continuous contraction-relaxation cycles of the heart require strong and stable connections of cardiac myocytes (CMs) with the extracellular matrix (ECM) to preserve sarcolemmal integrity. CM attachment to the ECM is mediated by integrin complexes localized at the muscle adhesion sites termed costameres. The ubiquitously expressed cytoskeletal protein talin (Tln) is a component of muscle costameres that links integrins ultimately to the sarcomere.

Modulation of caveolins, integrins and plasma membrane repair proteins in anthracycline-induced heart failure in rabbits.

Anthracyclines are chemotherapeutic drugs known to induce heart failure in a dose-dependent manner. Mechanisms involved in anthracycline cardiotoxicity are an area of relevant investigation. Caveolins bind, organize and regulate receptors and signaling molecules within cell membranes.

Postnatal Loss of Kindlin-2 Leads to Progressive Heart Failure.

Background: The striated muscle costamere, a multiprotein complex at the boundary between the sarcomere and the sarcolemma, plays an integral role in maintaining striated muscle structure and function. Multiple costamere-associated proteins, such as integrins and integrin-interacting proteins, have been identified and shown to play an increasingly important role in the pathogenesis of human cardiomyopathy. Kindlin-2 is an adaptor protein that binds to the integrin β cytoplasmic tail to promote integrin activation.

Integrins and integrin-related proteins in cardiac fibrosis.

Cardiac fibrosis is one of the major components of the healing mechanism following any injury of the heart and as such may contribute to both systolic and diastolic dysfunction in a range of pathophysiologic conditions. Canonically, it can occur as part of the remodeling process that occurs following myocardial infarction or that follows as a response to pressure overload. Integrins are cell surface receptors which act in both cellular adhesion and signaling.

Integrins and integrin-associated proteins in the cardiac myocyte.

Integrins are heterodimeric, transmembrane receptors that are expressed in all cells, including those in the heart. They participate in multiple critical cellular processes including adhesion, extracellular matrix organization, signaling, survival, and proliferation. Particularly relevant for a contracting muscle cell, integrins are mechanotransducers, translating mechanical to biochemical information.

Integrins protect cardiomyocytes from ischemia/reperfusion injury.

Ischemic damage is recognized to cause cardiomyocyte (CM) death and myocardial dysfunction, but the role of cell-matrix interactions and integrins in this process has not been extensively studied. Expression of α7β1D integrin, the dominant integrin in normal adult CMs, increases during ischemia/reperfusion (I/R), while deficiency of β1 integrins increases ischemic damage. We hypothesized that the forced overexpression of integrins on the CM would offer protection from I/R injury.

Talin1 has unique expression versus talin 2 in the heart and modifies the hypertrophic response to pressure overload.

Integrins are adhesive, signaling, and mechanotransduction proteins. Talin (Tln) activates integrins and links it to the actin cytoskeleton. Vertebrates contain two talin genes, tln1 and tln2.

New isoform-specific monoclonal antibodies reveal different sub-cellular localisations for talin1 and talin2.

Talins are adaptor proteins that connect the integrin family of cell adhesion receptors to cytoskeletal actin. Vertebrates express two closely related talins encoded by separate genes, and while it is well established that talin1 plays a key role in cell adhesion and spreading, little is known about the role of talin2. To facilitate such studies, we report the characterisation of 4 new isoform-specific talin mouse monoclonal antibodies that work in Western blotting, immuno-precipitation, immuno-fluorescence and immuno-histochemistry.

β1 integrin gene excision in the adult murine cardiac myocyte causes defective mechanical and signaling responses.

How mechanical signals are transmitted in the cardiac myocyte is poorly understood. In this study, we produced a tamoxifen-inducible mouse model in which β1 integrin could be reduced specifically in the adult cardiomyocyte, so that the function of this integrin could be assessed in the postnatal and mechanically stressed heart. The expression of β1 integrin was reduced to 35% of control levels, but function remained normal at baseline.

Integrins, focal adhesions, and cardiac fibroblasts.

How the myocardium undergoes geometric, structural, and molecular alterations that result in an end phenotype as might be seen in patients with dilated cardiomyopathy or after myocardial infarction is still poorly understood. Structural modification of the left ventricle, which occurs during these pathological states, results from long-term changes in loading conditions and is commonly referred to as "remodeling." Remodeling may occur from increased wall stress in the face of hypertensive heart disease, valvular disease, or, perhaps most dramatically, after permanent coronary occlusion.

Vinculin and talin: focus on the myocardium.

Cardiomyopathy is a heart muscle disease caused by decreased contractility of the ventricles leading to heart failure and premature death. Multiple conditions like ischemic heart disease (atherosclerosis), hypertension, diabetes, viral infection, alcohol abuse, obesity and genetic mutations can lead to cardiomyopathy. Single gene mutations in sarcomeric proteins, Z-disk-associated proteins, membrane/associated proteins, intermediate filaments, calcium cycle proteins as well as in modifier genes have been linked to cardiomyopathy.

Cardiac fibroblasts require focal adhesion kinase for normal proliferation and migration.

Migration and proliferation of cardiac fibroblasts (CFs) play an important role in the myocardial remodeling process. While many factors have been identified that regulate CF growth and migration, less is known about the signaling mechanisms involved in these processes. Here, we utilized Cre-LoxP technology to obtain focal adhesion kinase (FAK)-deficient adult mouse CFs and studied how FAK functioned in modulating cell adhesion, proliferation, and migration of these cells.

Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy.

Vinculin is a ubiquitously expressed multiliganded protein that links the actin cytoskeleton to the cell membrane. In myocytes, it is localized in protein complexes which anchor the contractile apparatus to the sarcolemma. Its function in the myocardium remains poorly understood.

High glucose enhances inducible nitric oxide synthase expression. Role of protein kinase C-betaII.

The aim was to determine whether high glucose levels interfere with nitric oxide (NO) production and inducible NO synthase (iNOS) protein expression in interleukin-1beta-stimulated vascular smooth muscle cells from normotensive Wistar Kyoto and spontaneously hypertensive rats. Cells were incubated with either normal (5.5 mM) or high (22 mM) d-glucose for 72 h and with interleukin-1beta (10 ng/ml) for the last 24 h.

Integrins, membrane-type matrix metalloproteinases and ADAMs: potential implications for cardiac remodeling.

The concept of myocardial remodeling links an initial pathological insult to a progressive geometric change of the ventricle. Currently, our concepts of the remodeling process have evolved to include not only changes in ventricular size and shape, but cellular and molecular remodeling, particularly as the ventricle evolves towards failure. In recent years, much attention has focused on the role of cell-extracellular matrix (ECM) connections in this process.

Profibrotic influence of high glucose concentration on cardiac fibroblast functions: effects of losartan and vitamin E.

Long-standing diabetes can result in the development of cardiomyopathy, which can be accompanied by myocardial fibrosis. Although exposure of cultured kidney and skin fibroblasts to high glucose (HG) concentration is known to increase collagen synthesis, little is known about cardiac fibroblasts (CFs). Therefore, we determined the influence of HG conditions on CF functions and the effects of losartan and vitamin E in these responses.