Deletion of Ptpn11 (Shp2) in Cardiomyocytes Causes Dilated Cardiomyopathy via Effects on the Extracellular Signal–Regulated Kinase/Mitogen-Activated Protein Kinase and RhoA Signaling Pathways

Abstract

Background-Heart failure is the leading cause of death in the United States. By delineating the pathways that regulate cardiomyocyte function, we can better understand the pathogenesis of cardiac disease. Many cardiomyocyte signaling pathways activate protein tyrosine kinases. However, the role of specific protein tyrosine phosphatases (PTPs) in these pathways is unknown. Methods and Results-Here, we show that mice with muscle-specific deletion of Ptpn11, the gene encoding the SH2 domain-containing PTP Shp2, rapidly develop a compensated dilated cardiomyopathy without an intervening hypertrophic phase, with signs of cardiac dysfunction appearing by the second postnatal month. Shp2-deficient primary cardiomyocytes are defective in extracellular signal-regulated kinase/mitogen-activated protein kinase (Erk/MAPK) activation in response to a variety of soluble agonists and pressure overload but show hyperactivation of the RhoA signaling pathway. Treatment of primary cardiomyocytes with Erk1/2-and RhoA pathway-specific inhibitors suggests that both abnormal Erk/MAPK and RhoA activities contribute to the dilated phenotype of Shp2-deficient hearts. Conclusions-Our results identify Shp2 as the first PTP with a critical role in adult cardiac function, indicate that in the absence of Shp2 cardiac hypertrophy does not occur in response to pressure overload, and demonstrate that the cardioprotective role of Shp2 is mediated via control of both the Erk/MAPK and RhoA signaling pathways. Key Words: cardiomyopathies Ⅲ heart diseases Ⅲ molecular biology Ⅲ myocardium Ⅲ myocytes Ⅲ signal transduction H eart failure is an emerging epidemic and a leading cause of death in the United States. 1 Delineating the signaling pathways that regulate normal survival, proliferation, and growth of cardiomyocytes and determining how these processes are deregulated are essential for us to understand the pathogenesis of cardiomyopathy and heart failure. Clinical Perspective p 1435Cardiomyocytes respond to a variety of soluble endocrine, paracrine, and autocrine factors, as well as solid-state signals, which in turn stimulate an array of membrane-bound receptors. Soluble agonists include classic growth factors such as heregulin, epidermal growth factor (EGF), and insulin-like growth factor-1 (IGF-1), which signal via receptor tyrosine kinases (RTKs), and cytokines and ligands for G-proteincoupled receptors, 2 which signal, at least in part, via nonreceptor protein tyrosine kinases (PTKs). Solid-state signals (eg, ligands for integrins) also can activate nonreceptor PTKs. Upon receptor activation, PTK-associated receptors activate a number of downstream signaling cascades, including the Ras/extracellular signal-regulated kinase (Erk) mitogen-activated protein kinase (MAPK) pathway, other MAPKs (eg, Received May 11, 2007; accepted January 2, 2008. Although many cardiomyocyte signaling pathways involve PTKs, the role of specific protein tyrosine phosphatases (PTPs) in normal cardiac development and disease remains largely obscure. Shp2, a nonreceptor...

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

“…We assessed the effects of cardiac Gab1 deletion on Gab1 downstream signaling in hearts of Gab1-cKO and Gab1-WT control mice after 2 weeks of TAC or sham operation. In agreement with previous studies, [28][29][30] TAC increased ERK1/2 phosphorylation in Gab1-WT mice compared with sham control, but this response was impaired in Gab1-cKO mice (Figures 3a and b). TAC also induced p38MAPK phosphorylation in Gab1-WT mice, and this TAC-induced phosphorylation of p38MAPK was further enhanced in Gab1-cKO mice.…”

“…It was reported that gain-of-function mutations in PTPN11 (encoded SHP2) 47,48 and RAF1 49,50 cause Noonan syndrome with hypertrophic cardiomyopathy, a genetic disorder in which the heart muscle becomes thick. In contrast, loss-of-function mutations of RAF1 in humans 51 or genetic deletion of SHP2 28,52 and Raf1 53 in mice cause DCM. As Gab1 is associated with SHP2 and regulates MAPK signaling, it is conceivable that loss of Gab1 could alter MAPK signaling, resulting in DCM.…”

Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome–associated PTPN11 mutation

“…Essential for development and the first PTP known to have a functional role in adult myocardium (16,17), SHP2 plays a key role in RAS/MAPK activation in response to most, if not all, receptor tyrosine kinase (RTK), cytokine receptor, GPCR, and integrin signaling pathways (18). Moreover, germline PTPN11 mutations cause 2 related, but distinguishable, syndromes that include congenital heart defects among their features.…”

RhoA protects the mouse heart against ischemia/reperfusion injury

“…In light of the multiple upstream regulators and downstream mediators of RhoA signaling, it is perhaps not surprising that its role in cardiac physiology and pathophysiology remains elusive (5). On the one hand, there are published data demonstrating that high levels of RhoA expression in cardiomyocytes can induce apoptosis (6) and cardiomyopathy (7,8) and that the well-characterized RhoA effector Rho kinase (ROCK) has deleterious effects on the heart (9-12). On the other hand, expression of RhoA at a more physiological level can protect cardiomyocytes against apoptosis induced by H 2 O 2 or glucose deprivation (13) and inhibiting Rho leads to caspase-3 activation and apoptosis (14).…”