Arginyltransferase knockdown attenuates cardiac hypertrophy and fibrosis through TAK1-JNK1/2 pathway

Abstract

Myocardial hypertrophy, an inflammatory condition of cardiac muscles is a maladaptive response of the heart to biomechanical stress, hemodynamic or neurohormonal stimuli. Previous studies indicated that knockout of Arginyltransferase (ATE1) gene in mice and embryos leads to contractile dysfunction, defective cardiovascular development, and impaired angiogenesis. Here we found that in adult rat model, downregulation of ATE1 mitigates cardiac hypertrophic, cardiac fibrosis as well as apoptosis responses in the presence of cardiac stress i.e. renal artery ligation. On contrary, in wild type cells responding to renal artery ligation, there is an increase of cellular ATE1 protein level. Further, we have shown the cardioprotective role of ATE1 silencing is mediated by the interruption of TAK1 activitydependent JNK1/2 signaling pathway. We propose that ATE1 knockdown in presence of cardiac stress performs a cardioprotective action and the inhibition of its activity may provide a novel approach for the treatment of cardiac hypertrophy.

Liquiritin Attenuates Angiotensin II-Induced Cardiomyocyte Hypertrophy via ATE1/TAK1-JNK1/2 Pathway

“…These results suggested that ATE1 overexpression in H9c2 cells promoted hypertrophy induced by Ang II. These results were in line with the results reported previously [ 9 ]. After LIQ intervention, the cell surface area and the levels of ANP, BNP, and β -MHC decreased significantly ( P < 0.01).…”

“…These results partly explain how ATE1 gene deletion affects the phenotype of a normal embryonic heart. However, in response to increased cardiac stress, the expression of the ATE1 gene and protein in adult rats was strongly upregulated, and the loss of ATE1 gene expression in this type of cardiac cells suppressed the expression of genes that regulate cardiac hypertrophy [ 9 ]; this effect may be potentially related to downregulation of arginylation after ATE1 knockout or silencing, which makes the cells less sensitive to different stress factors [ 39 ]. Increasing evidence suggests that arginylation occurs as a response to a variety of stress, preferentially on damaged proteins [ 42 , 43 ].…”

“…After 24 h of culture, the H9c2 cells were then assigned to three groups: (1) control group: the cells were cultured normally; (2) Ang II group: the cells were treated with 1 μ M Ang II for 24 h; and (3) LIQ group: the cells were treated with 30 μ M LIQ for 1 h before Ang II administration. Each group was incubated in an incubator with 5% CO 2 at 37°C [ 9 , 19 ]. Ang II was dissolved in PBS, and LIQ was dissolved in DMSO, where the final concentration of DMSO was <0.1%.…”

“…Furthermore, multiple signaling pathways are involved in cardiac hypertrophy development, among which ATE1 is an important target and acts as a regulator of hypertrophic response [ 7 , 8 ]. A recent study showed that ATE1 regulates the expression of hypertrophic gene markers via the TAK1-JNK1/2 signaling pathway, which provides a potentially novel therapeutic target for treating cardiac hypertrophy [ 9 ].…”

Targeting fibrosis in the Duchenne Muscular Dystrophy mice model: an uphill battle

“…The TGFb-TAK1 pathway is a shared molecular pathway regulating TyrK, BRD and p38 MAPK signaling. Growing evidence supports the role of TAK1 as a significant regulator of TGFb signaling through the regulation of the profibrotic response in several systems [43][44][45][83][84][85][86][87]. Very recently, it has been shown that the action of Catalpol (an anti-inflammatory and antioxidant drug from Chinese medicinal herb Rehmannia) on DMD histopathology was due to its binding to TAK1 [88,89].…”