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Integrins are the necessary links to hypertrophic growth in cardiomyocytes.

Harston RK, Kuppuswamy D - J Signal Transduct (2011)

Bottom Line: The growth signaling pathways downstream of β(1) and β(3) integrins are well characterized.However, new integrin pathways responsible for inhibiting apoptosis induced by hemodynamic overload are emerging. β(1) and β(3) integrins activate differential survival signaling, yet both integrins initiate survival signaling downstream of ubiquitination and the kinase pathway including phosphoinositol-3-kinase (PI3K)/Akt.Further characterization of these integrin-signaling mechanisms may lead to drug targets to prevent decompensation to heart failure.

View Article: PubMed Central - PubMed

Affiliation: Cardiology Division, Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, SC 29425-2221, USA.

ABSTRACT
To compensate for hemodynamic overload of the heart, an event which stretches the myocardium, growth and survival signaling are activated in cardiac muscle cells (cardiomyocytes). Integrins serve as the signaling receptors of cardiomyocytes responsible for mechanotransduction toward intracellular signaling. The main integrin heterodimers on the cardiomyocyte surface are α(5)β(1) and α(v)β(3), and elimination of either β(1) or β(3) integrins impedes pressure-induced hypertrophic signaling and leads to increased mortality. The growth signaling pathways downstream of β(1) and β(3) integrins are well characterized. However, new integrin pathways responsible for inhibiting apoptosis induced by hemodynamic overload are emerging. β(1) and β(3) integrins activate differential survival signaling, yet both integrins initiate survival signaling downstream of ubiquitination and the kinase pathway including phosphoinositol-3-kinase (PI3K)/Akt. Further characterization of these integrin-signaling mechanisms may lead to drug targets to prevent decompensation to heart failure.

No MeSH data available.


Related in: MedlinePlus

Diagram of the collagen overlay model for integrin stimulation in cardiomyocytes with RGD peptide. Cardiomyocytes are plated on laminin-coated plates in media desired for optimal experimental conditions. For integrin stimulation under two-dimensional (2D) conditions (left side of the figure), RGD peptide is added directly in the media to stimulate integrin but with no FAC. For integrin stimulation and FAC formation, (figure on the right), media are removed and replaced with the type I collagen matrix mixed with RGD peptide and allowed to polymerize. Integrins are represented by grey cylinders in the figure.
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fig2: Diagram of the collagen overlay model for integrin stimulation in cardiomyocytes with RGD peptide. Cardiomyocytes are plated on laminin-coated plates in media desired for optimal experimental conditions. For integrin stimulation under two-dimensional (2D) conditions (left side of the figure), RGD peptide is added directly in the media to stimulate integrin but with no FAC. For integrin stimulation and FAC formation, (figure on the right), media are removed and replaced with the type I collagen matrix mixed with RGD peptide and allowed to polymerize. Integrins are represented by grey cylinders in the figure.

Mentions: As mentioned, integrin activation and FAC formation can be recapitulated in vitro by embedding laminin-plated adult cardiomyocytes in a collagen matrix with the integrin-stimulating peptide RGD, referred to as a 3D model (Figure 2). This model specifically activates integrins in a similar manner as in intact tissue when the RGD motif is exposed in the extracellular matrix. When the collagen polymerizes, the embedded RGD peptide can tether to the collagen matrix to induce the integrin heterodimers on the cell surface, the most prominent being β 3 and α5β1 [22]. To decipher signaling that is independent of the FAC formation, a 2D model can be used where RGD is added directly to media of laminin-plated cardiomyocytes. Without the stabilization provided by the polymerized collagen, the RGD is absorbed by the cardiomyocytes [32]. Devoid of the semisolid collagen matrix, RGD simply engages integrins without inducing FAC formation in the 2D model because integrins are unable to cluster and recruit focal adhesion proteins onto the cytoskeletal complex [22, 32]. Therefore, many integrin-mediated pathways requiring FAC formation for their activation are silent in this 2D model [22], such as ubiquitination [20]. On the other hand, the 3D collagen model is able to recapitulate the recruitment and activation of the β3 integrin and focal adhesion proteins, such as Src, FAK, Nck, Shc, and p130Cas, as observed in the hypertrophic animal models [22]. Importantly, introducing RGD to laminin-coated cardiomyocytes without collagen (2D model) does not cause the recruitment of these proteins to the FAC. It is also apparent that FAK is not phosphorylated during RGD treatment without FAC formation [22], indicating activation of FAK requires its recruitment to FAC. These studies lend to both pharmacological and adenoviral manipulations of cardiomyocytes, and methods have also been optimized to utilize cardiomyocytes from knockout murine models [20]. These cell culture models are important tools to decipher the intracellular signaling of integrins in cardiomyocytes.


Integrins are the necessary links to hypertrophic growth in cardiomyocytes.

Harston RK, Kuppuswamy D - J Signal Transduct (2011)

Diagram of the collagen overlay model for integrin stimulation in cardiomyocytes with RGD peptide. Cardiomyocytes are plated on laminin-coated plates in media desired for optimal experimental conditions. For integrin stimulation under two-dimensional (2D) conditions (left side of the figure), RGD peptide is added directly in the media to stimulate integrin but with no FAC. For integrin stimulation and FAC formation, (figure on the right), media are removed and replaced with the type I collagen matrix mixed with RGD peptide and allowed to polymerize. Integrins are represented by grey cylinders in the figure.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3101892&req=5

fig2: Diagram of the collagen overlay model for integrin stimulation in cardiomyocytes with RGD peptide. Cardiomyocytes are plated on laminin-coated plates in media desired for optimal experimental conditions. For integrin stimulation under two-dimensional (2D) conditions (left side of the figure), RGD peptide is added directly in the media to stimulate integrin but with no FAC. For integrin stimulation and FAC formation, (figure on the right), media are removed and replaced with the type I collagen matrix mixed with RGD peptide and allowed to polymerize. Integrins are represented by grey cylinders in the figure.
Mentions: As mentioned, integrin activation and FAC formation can be recapitulated in vitro by embedding laminin-plated adult cardiomyocytes in a collagen matrix with the integrin-stimulating peptide RGD, referred to as a 3D model (Figure 2). This model specifically activates integrins in a similar manner as in intact tissue when the RGD motif is exposed in the extracellular matrix. When the collagen polymerizes, the embedded RGD peptide can tether to the collagen matrix to induce the integrin heterodimers on the cell surface, the most prominent being β 3 and α5β1 [22]. To decipher signaling that is independent of the FAC formation, a 2D model can be used where RGD is added directly to media of laminin-plated cardiomyocytes. Without the stabilization provided by the polymerized collagen, the RGD is absorbed by the cardiomyocytes [32]. Devoid of the semisolid collagen matrix, RGD simply engages integrins without inducing FAC formation in the 2D model because integrins are unable to cluster and recruit focal adhesion proteins onto the cytoskeletal complex [22, 32]. Therefore, many integrin-mediated pathways requiring FAC formation for their activation are silent in this 2D model [22], such as ubiquitination [20]. On the other hand, the 3D collagen model is able to recapitulate the recruitment and activation of the β3 integrin and focal adhesion proteins, such as Src, FAK, Nck, Shc, and p130Cas, as observed in the hypertrophic animal models [22]. Importantly, introducing RGD to laminin-coated cardiomyocytes without collagen (2D model) does not cause the recruitment of these proteins to the FAC. It is also apparent that FAK is not phosphorylated during RGD treatment without FAC formation [22], indicating activation of FAK requires its recruitment to FAC. These studies lend to both pharmacological and adenoviral manipulations of cardiomyocytes, and methods have also been optimized to utilize cardiomyocytes from knockout murine models [20]. These cell culture models are important tools to decipher the intracellular signaling of integrins in cardiomyocytes.

Bottom Line: The growth signaling pathways downstream of β(1) and β(3) integrins are well characterized.However, new integrin pathways responsible for inhibiting apoptosis induced by hemodynamic overload are emerging. β(1) and β(3) integrins activate differential survival signaling, yet both integrins initiate survival signaling downstream of ubiquitination and the kinase pathway including phosphoinositol-3-kinase (PI3K)/Akt.Further characterization of these integrin-signaling mechanisms may lead to drug targets to prevent decompensation to heart failure.

View Article: PubMed Central - PubMed

Affiliation: Cardiology Division, Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, SC 29425-2221, USA.

ABSTRACT
To compensate for hemodynamic overload of the heart, an event which stretches the myocardium, growth and survival signaling are activated in cardiac muscle cells (cardiomyocytes). Integrins serve as the signaling receptors of cardiomyocytes responsible for mechanotransduction toward intracellular signaling. The main integrin heterodimers on the cardiomyocyte surface are α(5)β(1) and α(v)β(3), and elimination of either β(1) or β(3) integrins impedes pressure-induced hypertrophic signaling and leads to increased mortality. The growth signaling pathways downstream of β(1) and β(3) integrins are well characterized. However, new integrin pathways responsible for inhibiting apoptosis induced by hemodynamic overload are emerging. β(1) and β(3) integrins activate differential survival signaling, yet both integrins initiate survival signaling downstream of ubiquitination and the kinase pathway including phosphoinositol-3-kinase (PI3K)/Akt. Further characterization of these integrin-signaling mechanisms may lead to drug targets to prevent decompensation to heart failure.

No MeSH data available.


Related in: MedlinePlus