Synthesis of Extracellular Matrix and Adhesion Through β
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            Integrins Are Critical for Fetal Ventricular Myocyte Proliferation

Hornberger, Lisa K.; Singhroy, Sandra; Cavallé‐Garrido, Tíscar; Tsang, Wendy; Keeley, Fred W.; Rabinovitch, Marlene

doi:10.1161/01.res.87.6.508

Cited by 56 publications

(41 citation statements)

References 54 publications

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“…Epidermal growth factor (EGF)-mediated proliferation of human fetal myocytes requires the coordinated expression of ECM proteins as well as ␤ 1 -integrins (52). Transfection of the ubiquitously expressed ␤ 1A -isoform, or the muscle-specific ␤ 1D -isoform, augmented atrial natriuretic factor (ANF) and myosin regulatory light chain 2v (MLC2v) promoter activity in neonatal rat ventricular myocytes (99).…”

Section: Integrin-dependent Signal Transduction and Cell Survivalmentioning

confidence: 99%

Costameres, focal adhesions, and cardiomyocyte mechanotransduction

Samarel¹

2005

American Journal of Physiology-Heart and Circulatory Physiology

252

201

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Samarel, Allen M. Costameres, focal adhesions, and cardiomyocyte mechanotransduction. Am J Physiol Heart Circ Physiol 289: H2291-H2301, 2005; doi: 10.1152/ajpheart.00749.2005.-Mechanotransduction refers to the cellular mechanisms by which load-bearing cells sense physical forces, transduce the forces into biochemical signals, and generate appropriate responses leading to alterations in cellular structure and function. This process affects the beat-to-beat regulation of cardiac performance but also affects the proliferation, differentiation, growth, and survival of the cellular components that comprise the human myocardium. This review focuses on the experimental evidence indicating that the costamere and its structurally related structure the focal adhesion complex are critical cytoskeletal elements involved in cardiomyocyte mechanotransduction. Biochemical signals originating from the extracellular matrix-integrin-costameric protein complex share many common features with those signals generated by growth factor receptors. The roles of key regulatory kinases and other muscle-specific proteins involved in mechanotransduction and growth factor signaling are discussed, and issues requiring further study in this field are outlined.focal adhesion kinase; proline-rich tyrosine kinase 2; integrin-linked kinase; protein kinase C; signal transduction; heart THE PROCESS OF MECHANOTRANSDUCTION refers to the cellular mechanisms by which load-bearing cells sense physical forces, transduce the forces into biochemical signals, and generate appropriate responses leading to alterations in cellular structure and function. Physical forces encountered by living cells include membrane stretch, gain and loss of adhesion, and compression due to an increase in pressure. The signal transduction pathways that are activated in response to mechanical forces include many unique components, as well as elements shared by other signaling pathways. Mechanotransduction in cardiomyocytes is particularly complex, in that individual muscle cells both respond to externally applied mechanical forces as well as generate internal loads that are transmitted to adjacent cells and their surrounding extracellular matrix (ECM). Mechanotransduction in both atrial and ventricular cardiomyocytes affects the beat-to-beat regulation of cardiac performance but also profoundly affects the proliferation, differentiation, growth, and survival of the cellular components that comprise the human myocardium. Understanding the cellular and molecular basis for mechanotransduction is therefore important to our overall understanding of cardiac structure and function in the normal and diseased heart.Observational studies conducted during the 1970s addressing the hypertrophic growth response of human myocardium to pathological changes in systolic and diastolic wall stress (42) fostered the development of experimental model systems with which to explore cardiomyocyte mechanotransduction in vivo and in vitro. These model systems now span the breadth of experimental cardiology...

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Section: Integrin-dependent Signal Transduction and Cell Survivalmentioning

confidence: 99%

Costameres, focal adhesions, and cardiomyocyte mechanotransduction

Samarel¹

2005

American Journal of Physiology-Heart and Circulatory Physiology

252

201

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“…[41][42][43][44] In this regard, epidermal growth factor (EGF)-mediated proliferation of human fetal ventricular myocytes has specifically been linked to adhesion through ␤ 1 integrins, particularly ␣ 1 ␤ 1 and ␣ 5 ␤ 1 . 42 ␤ 3 integrins did not appear to be involved in this proliferative response.…”

Section: Integrins In Cardiac Developmentmentioning

confidence: 99%

Integrins and the Myocardium

Ross

Borg

2001

Circulation Research

397

279

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Abstract-Extracellular matrix provides a structural, chemical, and mechanical substrate that is essential in cardiac development, growth, and responses to pathophysiological signals. Transmembrane receptors termed integrins provide a dynamic interaction of environmental cues and intracellular events. Integrins orchestrate multiple functions in the intact organism including organogenesis, regulation of gene expression, cell proliferation, differentiation, migration, and death. They are expressed in all cellular components of the cardiovascular system, including the vasculature, blood, cardiac myocytes and nonmuscle cardiac cells. The focus of this review will be on the role of integrins in the myocardium. We will provide background on integrin structure and function, discuss how the expression of integrins is critical to the form and function of the developing and postnatal myocardium, and review the known data on integrins as signaling molecules in the heart. Finally, we will offer insights to the future research directions into this important family of extracellular matrix receptors in the myocardium. Key Words: integrin Ⅲ myocardium Ⅲ extracellular matrix E xtracellular matrix (ECM) provides a structural, chemical, and mechanical substrate that is essential in cardiac development, growth, and responses to pathophysiological signals. Transmembrane receptors termed integrins provide a dynamic interaction of environmental cues and intracellular events. [1][2][3] Integrins orchestrate multiple functions in the intact organism including organogenesis, regulation of gene expression, cell proliferation, differentiation, migration, and death. They are expressed in all cellular components of the cardiovascular system, including the vasculature, blood, cardiac myocytes, and nonmuscle cardiac cells. The focus of this review will be on the role of integrins in the myocardium, because their function in the vasculature and platelets has been recently reviewed. 4,5 We will discuss how the expression of integrins is critical to the form and function of the myocardium, evaluate potential mechanisms of action of the integrins in the regulation of these processes, and offer insights to the future research directions into this important family of ECM receptors in the myocardium. Integrin StructureIntegrins are noncovalently associated heterodimeric transmembrane receptors composed of ␣ and ␤ subunits, with ␣ subunits ranging from 120 to 180 kDa whereas ␤ subunits are 90 to 110 kDa. 3,6 Historically, integrins were identified based on an initial series of experiments suggesting a physical association between fibronectin and the intracellular cytoskeleton. 7 Subsequently, studies were published from several laboratories that (1) identified glycoproteins having characteristics of membrane proteins, and (2) showed that antibodies which recognized these proteins could inhibit cellular adhesion. 8 -12 These observations led to the cloning of chick fibroblast cDNAs that encoded for a molecule involved in transmembrane linkage between f...

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“…Attempts to create permanent lines of proliferating cells that retain the proper cardiomyocyte phenotype have met with limited success [2][3][4][5]. Although various mitogens have been purported to stimulate proliferation of cardiomyocytes in different model systems (see [6] and [1] for thorough reviews), the limited availability of human cardiomyocytes has restricted study to relatively few investigations in vivo [7][8][9] or in vitro [10][11][12][13], and such studies were dependent on the availability of human fetal tissue sources.…”

Section: Introductionmentioning

confidence: 99%

Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway

McDevitt¹,

Laflamme

Murry

2005

Journal of Molecular and Cellular Cardiology

170

128

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Cardiomyocytes from common experimental animals rapidly exit the cell cycle upon isolation, impeding studies of basic cell biology and applications such as myocardial repair. Here we examined proliferation of cardiomyocytes derived from human and mouse embryonic stem (ES) cells. While mouse ES cell-derived cardiomyocytes showed little proliferation, human cardiomyocytes were highly proliferative under serum-free conditions (15-25% BrdU+/ sarcomeric actin+). The cells exhibited only a small serum dose-response, and proliferation gradually slowed with increasing differentiation of the cells. Neither cell density nor different matrix attachment factors affected cardiomyocyte proliferation. Blockade of phosphatidylinositol 3-kinase (PI 3-kinase) and Akt significantly reduced cardiomyocyte proliferation, whereas MEK inhibition had no effect. Antibody blocking of the insulin-like growth factor-1 (IGF-1) receptor significantly inhibited cardiomyocyte proliferation, while addition of IGF-1 or IGF-2 stimulated cardiomyocyte proliferation in a dose-dependent manner. Thus, cardiomyocytes derived from human ES cells proliferate extensively in vitro, and their proliferation appears to be mediated primarily via the PI 3-kinase/Akt signaling pathway, using the IGF-1 receptor as one upstream activator. This system should permit identification of regulatory pathways for human cardiomyocyte proliferation and may facilitate expansion of cardiomyocytes from human ES cells for therapeutic purposes.

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Synthesis of Extracellular Matrix and Adhesion Through β ₁ Integrins Are Critical for Fetal Ventricular Myocyte Proliferation

Cited by 56 publications

References 54 publications

Costameres, focal adhesions, and cardiomyocyte mechanotransduction

Costameres, focal adhesions, and cardiomyocyte mechanotransduction

Integrins and the Myocardium

Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway

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Synthesis of Extracellular Matrix and Adhesion Through β 1 Integrins Are Critical for Fetal Ventricular Myocyte Proliferation

Cited by 56 publications

References 54 publications

Costameres, focal adhesions, and cardiomyocyte mechanotransduction

Costameres, focal adhesions, and cardiomyocyte mechanotransduction

Integrins and the Myocardium

Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway

Contact Info

Product

Resources

About

Synthesis of Extracellular Matrix and Adhesion Through β ₁ Integrins Are Critical for Fetal Ventricular Myocyte Proliferation