Key result
Extracellular activation of MMP-2 accelerated collagen-I synthesis in rat cardiac fibroblasts, with FAK phosphorylation playing a pivotal role in this process.
Extracellular activation of MMP-2 stimulates collagen-I synthesis in cardiac fibroblasts via FAK phosphorylation, highlighting a potential molecular mechanism underlying cardiac fibrosis.
Should not change practice; leaves open MMP-2/FAK as a cardiac fibrosis pathway requiring in vivo validation.
Collagen-I is thought to be the main component of the extracellular matrix in cardiac fibrosis, the accumulation of which occurs with excessive activation of matrix metalloproteinase-2 (MMP-2). MMP-2 degrades the extracellular matrix; however, the relative importance of MMP-2 to collagen-I synthesis in cardiac fibroblasts remains unclear. We investigated whether extracellular activation of MMP-2 regulates collagen-I synthesis and phosphorylation of focal adhesion kinase (FAK) in rat cardiac fibroblasts. Primary cultures of rat cardiac fibroblasts were incubated with purified active MMP-2 to determine whether extracellular MMP-2 affects collagen-I synthesis and FAK phosphorylation in cardiac fibroblasts. Exogenous MMP-2 significantly stimulated FAK (Tyr397) phosphorylation and induced collagen-I expression in a time-dependent manner. Simultaneous treatment with the FAK inhibitor PF573228 abolished exogenous MMP-2-enhanced FAK (Tyr397) phosphorylation and collagen-I expression. Cells were then stimulated with norepinephrine (NE) to investigate whether endogenous MMP-2 could also induce collagen-I expression through FAK (Tyr397) phosphorylation. NE-stimulated endogenous MMP-2 activation in conditioned medium was significantly attenuated by simultaneous treatment with the MMP inhibitor PD166793. Similarly, NE-induced FAK (Tyr397) phosphorylation and collagen-I expression were significantly inhibited by simultaneous treatment with PD166793 or PF573228. Furthermore, MMP-2 knockdown induced by small interfering RNA (siRNA) significantly abolished endogenous MMP-2 expression and activation. MMP-2 siRNA significantly abolished NE-induced FAK (Tyr397) phosphorylation and collagen-I expression. These findings suggest that the extracellular activation of MMP-2 accelerated collagen-I synthesis in rat cardiac fibroblasts and that FAK phosphorylation (Tyr397) plays a pivotal role in MMP-2-stimulated collagen-I synthesis.
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Hori et al. (2012) studied Cardiac fibrosis. Exogenous MMP-2 and Norepinephrine vs. Inhibitors (PD166793, PF573228) or MMP-2 siRNA was evaluated on FAK (Tyr397) phosphorylation and collagen-I expression. Extracellular activation of MMP-2 accelerated collagen-I synthesis in rat cardiac fibroblasts, with FAK phosphorylation playing a pivotal role in this process.
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