Growth Arrest–Specific 6 Exacerbates Pressure Overload–Induced Cardiac Hypertrophy

Abstract

Growth arrest–specific 6 (GAS6) is a member of the vitamin K–dependent protein family that is involved in the regulation of the cardiovascular system, including vascular remodeling, homeostasis, and atherosclerosis. However, there is still no study that systemically elucidates the role of GAS6 in cardiac hypertrophy. Here, we found that GAS6 was upregulated in human dilated cardiomyopathic hearts, hypertrophic murine hearts, and angiotensin II–treated cardiomyocytes. Next, we examined the influence of GAS6 expression in response to a cardiac stress by inducing chronic pressure overload with aortic banding in wild-type and GAS6-knockout mice or cardiac-specific GAS6 overexpressing mice. Under basal conditions, the GAS6-knockout mice had normal left ventricular structure and function but after aortic banding, the mice demonstrated less hypertrophy, fibrosis, and contractile dysfunction when compared with wild-type mice. Conversely, cardiac-specific overexpression of GAS6 exacerbated aortic banding–induced cardiac hypertrophy, fibrosis, and dysfunction. Furthermore, we demonstrated that GAS6 activated the mitogen-activated protein kinase kinase 1/2–extracellular signal-regulated kinase 1/2 pathway during pressure overload–induced cardiac hypertrophy, and the pharmacological mitogen-activated protein kinase kinase 1/2 inhibitor U0126 almost completely reversed GAS6 overexpression–induced cardiac hypertrophy and fibrosis, resulting in improved cardiac function. Collectively, our data support the notion that GAS6 impairs ventricular adaptation to chronic pressure overload by activating mitogen-activated protein kinase kinase 1/2–extracellular signal-regulated kinase 1/2 signaling. Our findings suggest that strategies to reduce GAS6 activity in cardiac tissue may be a novel approach to attenuate the development of congestive heart failure.

Smad Nuclear Interacting Protein 1 Acts as a Protective Regulator of Pressure Overload‐Induced Pathological Cardiac Hypertrophy

“…MyLab 30CV ultrasound (Biosound Esaote Inc) was used for echocardiography as previously described . After mice were anesthetized with 1.5% to 2% isoflurane, the parameters of mouse heart were measured from parasternal short‐axis view and parasternal long‐axis view at a frame rate of 120 Hz.…”

“…As previously described, neonatal rat cardiomyocytes (NRCMs) were isolated from 1‐ to 2‐day‐old Sprague–Dawley neonatal rats. First, rats were euthanized by swift decapitation and the hearts were immediately excised and minced.…”

“…Finally, after removing the fibroblast using a differential attachment technique, NRCMs were seeded at a density of 1×10 6 cells/well onto 6‐well culture plates coated with gelatin in DMEM/F12 medium supplemented with 20% fetal bovine serum, bromodeoxyuridine (0.1 mmol/L, to inhibit the proliferation of cardiac fibroblasts), and penicillin/streptomycin. Two days later, the culture medium was replaced to serum‐free DMEM/F12 for 12 hours prior to stimulation with angiotensin II (Ang II, 100 nmol/L) or PBS, which was administered for 24 and 48 hours to induce cardiomyocyte hypertrophy.…”

“…Cardiac hypertrophy is an adaptive process of cardiac muscle in response to diverse biomechanical loads, such as hypertension, endocrine imbalance, and myocardium infarction . Enduring hypertrophy is followed by increased cardiac fibrosis, cell death, and contractile dysfunction, eventually developing into heart failure …”

“…C ardiac hypertrophy is an adaptive process of cardiac muscle in response to diverse biomechanical loads, such as hypertension, endocrine imbalance, and myocardium infarction. 1,2 Enduring hypertrophy is followed by increased cardiac fibrosis, cell death, and contractile dysfunction, eventually developing into heart failure. 3 Recently, it has been proven that several transcription regulators such as nuclear factor-jB (NF-jB), GATA transcription factors, nuclear factor of activated T cells, myocardium-related factor A, and myocyte enhancer factor-2 were activated in development of cardiac hypertrophy, which could induce the expression of hypertrophic genes promoting pathological cardiac hypertrophy.…”