Abstract
Cardiac fibrosis, a pathological condition due to excessive extracellular matrix (ECM) deposition in the myocardium, is associated with nearly all forms of heart disease. The processes and mechanisms that regulate cardiac fibrosis are not fully understood. In response to cardiac injury, macrophages undergo marked phenotypic and functional changes and act as crucial regulators of myocardial fibrotic remodeling. Here we show that the mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5) in macrophages is involved in pressure overload-induced cardiac fibrosis. Cardiac pressure overload resulting from transverse aortic constriction (TAC) leads to the upregulation of Mkp-5 gene expression in the heart. In mice lacking MKP-5, p38 MAPK and JNK were hyperactivated in the heart, and TAC-induced cardiac hypertrophy and myocardial fibrosis were attenuated. MKP-5 deficiency upregulated the expression of the ECM-degrading matrix metalloproteinase-9 (Mmp-9) in the Ly6Clow (M2-type) cardiac macrophage subset. Consistent with in vivo findings, MKP-5 deficiency promoted MMP-9 expression and activity of pro-fibrotic macrophages in response to IL-4 stimulation. Furthermore, using pharmacological inhibitors against p38 MAPK, JNK, and ERK, we demonstrated that MKP-5 suppresses MMP-9 expression through a combined effect of p38 MAPK/JNK/ERK, which subsequently contributes to the inhibition of ECM-degrading activity. Taken together, our study indicates that pressure overload induces MKP-5 expression and facilitates cardiac hypertrophy and fibrosis. MKP-5 deficiency attenuates cardiac fibrosis through MAPK-mediated regulation of MMP-9 expression in Ly6Clow cardiac macrophages.
Highlights
Cardiac fibrosis, a common pathophysiologic process associated with most heart diseases, is characterized by excessive extracellular matrix (ECM) deposition and expansion of the interstitium in the myocardium [1, 2]
Given that MKPs inactivate the mitogen-activated protein kinase (MAPK) through direct dephosphorylation [21], we assessed whether MAP kinase phosphatase-5 (MKP-5) regulates MAPK activity in the mouse left ventricle by measuring the phosphorylation of the MAPKs in cardiac tissues of Mkp-5+/+ and Mkp-5-/- mice after either sham or transverse aortic constriction (TAC) surgery
To investigate whether MKP-5 is involved in regulating Ly6Clow macrophages in response to pressure overload-induced cardiac fibrosis, we examined the expression of MKP-5 in Fluorescence-Activated Cell Sorting (FACS)-sorted
Summary
A common pathophysiologic process associated with most heart diseases, is characterized by excessive extracellular matrix (ECM) deposition and expansion of the interstitium in the myocardium [1, 2]. The collagen-based network of cardiac ECM proteins mainly consists of type I and III collagens, in addition to glycosaminoglycans, glycoproteins, and proteoglycans [1, 2]. This intricate network of cardiac ECM proteins functions as a scaffold for the myocardium and plays a critical role in transmitting the contractile force [1, 2, 4]. Under pathophysiological conditions, increased collagen deposition in the fibrotic myocardium disrupts the homeostasis of ECM turnover, leading to profound structural and functional impairment of the heart [5]. Targeting cardiac ECM turnover to maintain the balance of collagen homeostasis is very important in preventing and managing cardiac fibrotic remodeling
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