Abstract
Nemo-like kinase (NLK) is an evolutionary conserved serine/threonine protein kinase implicated in development, proliferation and apoptosis regulation. Here we identified NLK as a gene product induced in the hearts of mice subjected to pressure overload or myocardial infarction injury, suggesting a potential regulatory role with pathological stimulation to this organ. To examine the potential functional consequences of increased NLK levels, cardiac-specific transgenic mice with inducible expression of this gene product were generated, as well as cardiac-specific Nlk gene-deleted mice. NLK transgenic mice demonstrated baseline cardiac hypertrophy, dilation, interstitial fibrosis, apoptosis and progression towards heart failure in response to two surgery-induced cardiac disease models. In contrast, cardiac-specific deletion of Nlk from the heart, achieved by crossing a Nlk-loxP allele containing mouse with either a mouse containing a β-myosin heavy chain promoter driven Cre transgene or a tamoxifen inducible α-myosin heavy chain promoter containing transgene driving a MerCreMer cDNA, protected the mice from cardiac dysfunction following pathological stimuli. Mechanistically, NLK interacted with multiple proteins including the transcription factor Stat1, which was significantly increased in the hearts of NLK transgenic mice. These results indicate that NLK is a pathological effector in the heart.
Highlights
The adult mammalian heart hypertrophies when faced with a myriad of pathological insults such as hypertension, ischemic heart disease, viral myocarditis and valvular insufficiency [1]
We suspected that Nemo-like kinase (NLK) might play a regulatory role in the heart given an observed upregulation of its expression following 2 weeks of pressure overload hypertrophy induced by transverse aortic constriction (TAC) and 1 week after myocardial infarction (MI) injury (Fig 1A and 1B)
Myocytes isolated from neonatal rat hearts were the predominant source of NLK mRNA compared with the nonmyocyte fraction (Fig 1C)
Summary
The adult mammalian heart hypertrophies when faced with a myriad of pathological insults such as hypertension, ischemic heart disease, viral myocarditis and valvular insufficiency [1]. Numerous studies have shown that cardiac hypertrophy is a temporary and adaptive response that reduces wall stress in an attempt to preserve cardiac function [2]. Prolonged cardiac hypertrophy is maladaptive and can eventually lead to ventricular dysfunction and heart failure characterized by increased rates of myocyte apoptosis, fibrosis and chamber dilation [2]. Multiple signaling pathways are typically involved in mediating the cardiac hypertrophic response, which are initiated by secreted neuroendocrine factors and their membrane-bound receptors with associated G-proteins. PLOS ONE | DOI:10.1371/journal.pone.0164897 October 20, 2016
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