Mnk1 (Mitogen-Activated Protein Kinase–Interacting Kinase 1) Deficiency Aggravates Cardiac Remodeling in Mice

Abstract

Identifying the key factor involved in cardiac remodeling is critically important for developing novel strategies to protect against heart failure. Here, the role of Mnk1 (mitogen-activated protein kinase–interacting kinase 1) in cardiac remodeling was clarified. Cardiac remodeling was induced by transverse aortic constriction in Mnk1-knockout mice and their wild-type control mice. After 4 weeks of transverse aortic constriction, Mnk1-knockout mice developed exaggerated cardiac hypertrophy, fibrosis, dysfunction, and cardiomyocyte apoptosis and showed increased ERK1/2 (extracellular signal–regulated kinase 1/2) activation along with reduced sprouty2 expression. In line with the in vivo studies, Mnk1 knockdown by Mnk1 siRNA transfection induced exaggerated angiotensin II–induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes (NRVMs). Moreover, adenovirus-mediated overexpression of Mnk1 in NRVMs protected cardiomyocytes from angiotensin II–induced hypertrophy. In addition, overexpression of sprouty2 rescued NRVMs with Mnk1 knockdown from angiotensin II–induced hypertrophy. In accordance with the in vivo studies, as compared with the control group, Mnk1 knockdown led to hyperphosphorylation of ERK1/2 and suppression of the sprouty2 expression in angiotensin II–treated NRVMs; furthermore, Mnk1 overexpression led to hypophosphorylation of ERK1/2 in angiotensin II–treated NRVMs. In addition, sprouty2 overexpression suppressed the activation of ERK1/2 in angiotensin II–treated NRVMs with Mnk1 knockdown. Impressively, MnK1-knockout mice with overexpression of sprouty2 exhibited signs of a blunted cardiac hypertrophic response. Mnk1 likely carries out a suppressive function in cardiac hypertrophy via regulating the sprouty2/ERK1/2 pathway. It implicates Mnk1 in the development of cardiac remodeling.

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“…Cardiac functions were measured in our laboratory [14, 15]. Images of parasternal short axis were obtained at the mid-papillary muscle level under M mode.…”

“…The heart slides were obtained with methods previously described [14, 15]. Hematoxylin and eosin (HE) staining was performed to assess the cardiomyocyte cross-sectional area (CSA) and to observe the morphology of striated muscle.…”

“…NRCM were prepared in our laboratory following the method as described previously [15]. NRCM were treated with high glucose or M for 36 h. The culture medium was discarded, cell climbing was washed with PBS, and then the NRCM were fixed with 4% paraformaldehyde for 15 min at room temperature.…”

“…Total protein was extracted and transferred to PVDF membrane as previously described [15]. The next day, blots were incubated with secondary antibody labeled with horse radish peroxidase for 1 h. ECL working solution was added for protein blot scanning.…”

“…Total RNA and cDNA were prepared according to the previous description [14, 15]. We used 20  μ l reactions according to the standard protocol of the manufacturer and ran the cycle ((95°C/5 min + 45 × (95°C/10 sec + 60°C/10 sec + 72/10s) + 95°C/5 sec + 60°C/1 min + 97°C/0.11 sec) + 40°C/10 min).…”