β ₁ Integrins Participate in the Hypertrophic Response of Rat Ventricular Myocytes

Abstract

Abstract-Multiple signaling pathways have been implicated in the hypertrophic response of ventricular myocytes, yet the importance of cell-matrix interactions has not been extensively examined. Integrins are cell-surface molecules that link the extracellular matrix to the cellular cytoskeleton. They can function as cell signaling molecules and transducers of mechanical information in noncardiac cells. Given these properties and their abundance in cardiac cells, we evaluated the hypothesis that ␤ 1 integrin function is involved in the ␣ 1 -adrenergic mediated hypertrophic response of neonatal rat ventricular myocytes. The hypertrophic response of this model required interaction with extracellular matrix proteins. Specificity of these results was confirmed by demonstrating that ventricular myocytes plated onto an anti-␤ 1 integrin antibody supported the hypertrophic gene response. Adenovirus-mediated overexpression of ␤ 1 integrin augmented the myocyte hypertrophic response when assessed by protein synthesis and atrial natriuretic factor production, a marker gene of hypertrophic induction. DNA synthesis was not altered by integrin overexpression. Transfection of cultured cardiac myocytes with either the ubiquitously expressed ␤ 1A integrin or the cardiac/skeletal muscle-specific ␤ 1 isoform (␤ 1D ) activated reporter expression from both the atrial natriuretic factor and myosin light chain-2 ventricular promoters, genetic markers of ventricular cell hypertrophy. Finally, suppression of integrin signaling by overexpression of free ␤ 1 integrin cytoplasmic domains inhibited the adrenergically mediated atrial natriuretic factor response. These findings show that integrin ligation and signaling are involved in the cardiac hypertrophic response pathway. (Circ Res. 1998;82:1160-1172.)Key Words: hypertrophy Ⅲ myocardium Ⅲ extracellular matrix Ⅲ integrin Ⅲ myocyte M echanical stress on the heart from either pressure or volume loading can cause hypertrophy of the myocardium to optimize cardiac performance. Results from in vivo studies and cell culture models have indicated that morphological hypertrophy coincides with a cascade of intracellular biochemical signals.

A Role for the Extracellular Signal-regulated Kinase and p38 Mitogen-activated Protein Kinases in Interleukin-1β-stimulated Delayed Signal Tranducer and Activator of Transcription 3 Activation, Atrial Natriuretic Factor Expression, and Cardiac Myocyte Morphology

“…This is in general agreement with the levels of ANF expression induced by other hypertrophic stimuli. For example, MAPK/ERK kinase-1 overexpression and phenylephrine and endothelin-1 stimulation results in ANF positively stained myocytes that range from 20 to 75% of total cells (7,(43)(44)(45). SB203580 (10 M) pretreatment of IL-1␤-stimulated cells partially inhibited ANF positively stained cells to 14 Ϯ 2% (Fig.…”

Osteopontin: A Protective Mediator of Cardiac Fibrosis?

“…OP is a well-characterized ligand of ␤ 1 -integrin receptors, which are involved in the adrenergically mediated atrial natriuretic peptide (hypotrophic) response in cardiomyocytes. 16 Xie et al 12 observed a suppressed atrial natriuretic peptide response in OP Ϫ/Ϫ hearts, too. Taken together, these findings suggest that OP is important for physiologically "intact" integrin-dependent cell functions essential for the response to increased cardiac load and injury in cardiomyocytes and fibroblasts.…”

Role of the integrin-linked kinase/PINCH1/alpha-parvin complex in cardiac myocyte hypertrophy

“…Moreover, FN-induced hypertrophy depended on intact integrin signaling, as evidenced by inhibition with anti-b1-integrin antibody, [26][27][28] and potentiated hypertrophy induced by the alphaadrenergic agonist PE. 29 In this study, we examine the hypothesis that FN and PE stimulation regulate the expression and localization of ILK, PARVA and PINCH1 proteins in cardiac myocytes where they may play a role in promoting cellular survival and transducing extracellular signals leading to hypertrophy.…”