-
[show abstract]
[hide abstract]
ABSTRACT: 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. Clinical practice guidelines have been formulated by the American Heart Association and the Heart Failure Association of America on how to genetically evaluate patients with cardiomyopathy. To illustrate the concept that alterations in genes cause cardiovascular disease, this review will focus on two membrane-associated proteins, vinculin and talin. We will discuss the general function of vinculin/metavinulin as well as talin1 and talin2, with emphasis on what is understood about their role in the cardiac myocyte and in whole heart.
Journal of Investigative Medicine 12/2009; 57(8):849-55. · 1.96 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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. A fundamental derangement of myocyte function is the most common perception for the basis of remodeling, but the role of cells in the heart other than the muscle cell must, of course, be considered. Although studies of the myocyte have been extensive, cardiac fibroblasts have been studied less than myocytes. The fibroblast has a broad range of functions in the myocardium ranging from elaboration and remodeling of the extracellular matrix to communication of a range of signals within the heart, including electrical, chemical, and mechanical ones. Integrins are cell surface receptors that are instrumental in mediating cell-matrix interactions in all cells of the organism, including all types within the myocardium. This review will focus on the role of integrins and related proteins in the remodeling process, with a particular emphasis on the cardiac fibroblast. We will illustrate this function by drawing on 2 unique mouse models with perturbation of proteins linked to integrin function.
Journal of Investigative Medicine 12/2009; 57(8):856-60. · 1.96 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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. Treatment of FAK(flox/flox) CFs with Ad/Cre virus caused over 70% reduction of FAK protein levels within a cell population. FAK-deficient CFs showed no changes in focal adhesions, cell morphology, or protein expression levels of vinculin, talin, or paxillin; proline-rich tyrosine kinase 2 (Pyk2) expression and activity were increased. Knockdown of FAK protein in CFs increased PDGF-BB-induced proliferation, while it reduced PDGF-BB-induced migration. Adhesion to fibronectin was not altered. To distinguish between the function of FAK and Pyk2, FAK function was inhibited via adenoviral-mediated overexpression of the natural FAK inhibitor FAK-related nonkinase (FRNK). Ad/FRNK had no effect on Pyk2 expression, inhibited the PDGF-BB-induced migration, but did not change the PDGF-BB-induced proliferation. FAK deficiency had only modest effects on increasing PDGF-BB activation of p38 and JNK MAPKs, with no alteration in the ERK response vs. control cells. These results demonstrate that FAK is required for the PDGF-BB-induced migratory response of adult mouse CFs and suggest that FAK could play an essential role in the wound-healing response that occurs in numerous cardiac pathologies.
AJP Heart and Circulatory Physiology 02/2009; 296(3):H627-38. · 3.71 Impact Factor
-
Alice E Zemljic-Harpf,
Joel C Miller,
Scott A Henderson,
Adam T Wright, Ana Maria Manso,
Laila Elsherif,
Nancy D Dalton,
Andrea K Thor,
Guy A Perkins,
Andrew D McCulloch,
Robert S Ross
[show abstract]
[hide abstract]
ABSTRACT: 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. Therefore, we developed a mouse model with cardiac-myocyte-specific inactivation of the vinculin (Vcl) gene by using Cre-loxP technology. Sudden death was found in 49% of the knockout (cVclKO) mice younger than 3 months of age despite preservation of contractile function. Conscious telemetry documented ventricular tachycardia as the cause of sudden death, while defective myocardial conduction was detected by optical mapping. cVclKO mice that survived through the vulnerable period of sudden death developed dilated cardiomyopathy and died before 6 months of age. Prior to the onset of cardiac dysfunction, ultrastructural analysis of cVclKO heart tissue showed abnormal adherens junctions with dissolution of the intercalated disc structure, expression of the junctional proteins cadherin and beta1D integrin were reduced, and the gap junction protein connexin 43 was mislocalized to the lateral myocyte border. This is the first report of tissue-specific inactivation of the Vcl gene and shows that it is required for preservation of normal cell-cell and cell-matrix adhesive structures.
Molecular and Cellular Biology 12/2007; 27(21):7522-37. · 5.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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. In this review, we will specifically delineate how cell membrane-linked molecules of three classes: integrins, membrane-type matrix metalloproteinases, and ADAMs (A Disintegrin And Metalloproteinase) might play crucial roles in myocardial remodeling. These molecules are essential for cell-ECM adhesion, cell signaling, matrix modification, and proteolysis of surface receptors. Our goal is to put forth concepts on how they might interrelate to modulate the remodeling process in the heart.
Cardiovascular Research 03/2006; 69(3):574-84. · 6.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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. We cultured rat CFs in either normal glucose (NG; 5.5 mM) or HG (25 mM) media and assessed changes in protein and collagen synthesis, matrix metalloproteinase (MMP) activity, and levels of mRNA for ANG II type 1 (AT(1)) receptors. Results indicate that HG-level CFs synthesized more protein and collagen, and these effects were not due to changes in osmotic pressure. The addition of ANG II stimulated protein and collagen synthesis in NG-concentration but not HG-concentration CFs. Interestingly, losartan pretreatment blocked the HG- or ANG II-induced increases in both protein and collagen synthesis. HG or ANG II decreased total MMP activity. Decreases in MMP activity were blocked by losartan. AT(1) mRNA levels were upregulated with HG concentration. Vitamin E pretreatment blocked the effects of HG on total protein synthesis and stimulated MMP activity. Results suggest that HG levels may promote fibrosis by increasing CF protein and collagen synthesis and decreasing MMP activity. HG levels may cause these effects via the upregulation of AT(1) receptors, which can be blocked by losartan. However, vitamin E can alter HG concentration-induced changes in CF functions independently of AT(1) mRNA levels.
AJP Heart and Circulatory Physiology 02/2005; 288(1):H227-34. · 3.71 Impact Factor
