Targeted Expression of Receptor-Associated Late Transducer Inhibits Maladaptive Hypertrophy via Blocking Epidermal Growth Factor Receptor Signaling

Abstract

Abstract-Receptor-associated late transducer (RALT) is a feedback inhibitor of epidermal growth factor receptor signaling. RALT has been shown previously to be induced in the ischemic heart and to promote cardiomyocyte apoptosis in vitro. However, the role of RALT in cardiac hypertrophy remains unclear. We hypothesized that forced expression of RALT in the murine heart would protect the heart against cardiac hypertrophy in vivo. We investigated the effect of cardiac overexpression of rat RALT on cardiac hypertrophy induced by angiotensin II and isoproterenol in RALT transgenic mice and wild-type littermates. The extent of cardiac hypertrophy was assessed by 2D and M-mode echocardiography as well as by molecular and pathological analyses of cardiac samples. Constitutive expression of rat RALT in cardiac myocytes of murine heart attenuated both hypertrophic and inflammatory responses and preserved cardiac function. These beneficial effects were associated with the attenuation of the epidermal growth factor receptor-dependent cascade that was triggered by angiotensin II and isoproterenol stimulation. Additional evidence demonstrated that RALT expression blocked fibrosis in vivo and collagen synthesis in vitro. Therefore, cardiac overexpression of RALT improves cardiac function and inhibits maladaptive hypertrophy, inflammation, and fibrosis through attenuating epidermal growth factor receptor-dependent signaling. Key Words: RALT Ⅲ EGFR Ⅲ ERK1/2 Ⅲ cardiac hypertrophy Ⅲ heart failure Ⅲ fibrosis C ardiac hypertrophy is a response of the myocardium to increased workload, characterized by increased myocardial mass with extracellular matrix accumulation. 1,2 Although initially a beneficial adaptive response, prolonged hypertrophy may result in ventricular dilatation and heart failure. 3,4 One evolving concept is that the underlying signaling mechanism, rather than the presence of hypertrophy alone, may determine the functional outcome of cardiac hypertrophy. Thus, it is important to define and modulate the specific signaling mechanism activated by each hypertrophic stimulus and its effect on the cardiac phenotype.Epidermal growth factor receptor (EGFR) transactivation is an important step in the activation of downstream tyrosine kinases and serves as a scaffold for various signaling molecules in cardiac myocytes. 5 Inhibition of EGFR activation by its inhibitor AG1478 and the metalloproteinase inhibitor BB94 significantly attenuated cardiac hypertrophy in vitro and in vivo. 6,7 However, neither systemic effects of these interventions nor nonspecific effects of the chemical inhibitors can be excluded. Indeed, Kagiyama et al 8 showed that inhibition of EGFR by antisense oligonucleotides in mice caused a significant reduction of blood pressure, which could secondarily affect the extent of cardiac hypertrophy. These observations prompted us to investigate a molecular target that specifically blocks EGFR transactivation for inhibiting cardiac hypertrophy and heart failure. One such protein is receptor-associated late transduc...

Regulator of G protein signaling 5 protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload

“…In an attempt to elucidate the mechanisms underlying the inhibitory effect of Rgs5 on fibrosis, we analyzed key components of TGF-β1/Smad signal transduction. Blockade of this signaling pathway was predicted to blunt fibrosis (19). In line with these notions, our data suggest that Rgs5 abrogates Smad 2 phosphorylation and Smad 2/3 translocation in both cultured cardiac fibroblasts and hypertrophied hearts, thus inhibiting collagen synthesis and fibrosis.…”

“…Protein and collagen synthesis were assessed by [ 3 H]-leucine and [ 3 H]-proline incorporation as described previously (19,20). For the surface areas, the cells were fixed with 3.7% formaldehyde in PBS solution, permeabilized in 0.1% Triton X-100 in PBS solution, and stained with α-actinin (Sigma) at a dilution of 1:100 by standard immunocytochemical techniques.…”

Epidermal Growth Factor Receptor Transactivation: Mechanisms, Pathophysiology, and Potential Therapies in the Cardiovascular System

“…Earlier studies with antisense infusion demonstrated suppression of left ventricular hypertrophy in SHR and in rats with AngII infusion (49; 50). In addition, transgenic mice overexpressing receptor-associated late transducer, a feedback inhibitor of EGFR signaling, do not develop AngII-induced cardiac hypertrophy (98). As shown in culture, cardiac hypertrophy is attenuated with an ADAM inhibitor in mice with AngII infusion (90).…”

LIM and Cysteine-Rich Domains 1 Regulates Cardiac Hypertrophy by Targeting Calcineurin/Nuclear Factor of Activated T Cells Signaling

“…1,2 Although initially a beneficial adaptive response, prolonged hypertrophy may result in ventricular dilatation and heart failure, which is increasing in prevalence and is a debilitating disease with high rates of mortality and morbidity. [3][4][5][6] However, antihypertensive therapies and aortic valve replacement are the only 2 treatments proven to effectively reverse both structural and functional cardiac abnormalities associated with pathological cardiac hypertrophy. Understanding the underlying processes regulating cardiac remodeling will allow us to identify specific new therapies to improve the long-term outcomes of pathological cardiac hypertrophy in patients.…”