Abstract
The p47phox is a key regulatory subunit of Nox2-containing NADPH oxidase (Nox2) that by generating reactive oxygen species (ROS) plays an important role in Angiotensin II (AngII)-induced cardiac hypertrophy and heart failure. However, the signalling pathways of p47phox in the heart remains unclear. In this study, we used wild-type (WT) and p47phox knockout (KO) mice (C57BL/6, male, 7-month-old, n = 9) to investigate p47phox-dependent oxidant-signalling in AngII infusion (0.8 mg/kg/day, 14 days)-induced cardiac hypertrophy and cardiomyocyte apoptosis. AngII infusion resulted in remarkable high blood pressure and cardiac hypertrophy in WT mice. However, these AngII-induced pathological changes were significantly reduced in p47phox KO mice. In WT hearts, AngII infusion increased significantly the levels of superoxide production, the expressions of Nox subunits, the expression of PKCα and C-Src and the activation of ASK1 (apoptosis signal-regulating kinase 1), MKK3/6, ERK1/2, p38 MAPK and JNK signalling pathways together with an elevated expression of apoptotic markers, i.e., γH2AX and p53 in the cardiomyocytes. However, in the absence of p47phox, although PKCα expression was increased in the hearts after AngII infusion, there was no significant activation of ASK1, MKK3/6 and MAPKs signalling pathways and no increase in apoptosis biomarker expression in cardiomyocytes. In conclusion, p47phox-dependent redox-signalling through ASK1, MKK3/6 and MAPKs plays a crucial role in AngII-induced cardiac hypertrophy and cardiomyocyte apoptosis.
Highlights
Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, or Nox) is a membrane-bound enzyme that by generating reactive oxygen species (ROS) plays important role in the regulation of cellular function
We investigated the role of p47phox and its oxidant-signalling pathways in the hearts using a murine model of Angiotensin II (AngII)-infusion-induced cardiac hypertrophy and cardiomyocyte apoptosis in WT and p47phox KO mice
Our results suggested that p47phox oxidant-signalling through apoptosis signal-regulating kinase 1 (ASK1), MKK3/6 and mitogen-activated protein kinases (MAPKs) played a vital role in mediating cardiac hypertrophic response and the expression of apoptotic markers in cardiomyocytes in response to AngII challenge
Summary
Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, or Nox) is a membrane-bound enzyme that by generating reactive oxygen species (ROS) plays important role in the regulation of cellular function. NADPH oxidase (Nox2) has been found to play an essential role in mediating AngIIinduced cardiac hypertrophy and failure [1,2,3,4,5]. Nox is a multi-subunit enzyme consisting of two membrane-bound subunits, p22phox and Nox ( named gp91phox ), and four cytosolic regulatory subunits, i.e., p40phox , p47phox , p67phox and rac. The p47phox is a key regulatory subunit of Nox enzyme [2,6,7]. The phosphorylation of p47phox initiates the process of coordination and association of regulatory subunits with membrane-bound p22phox /Nox complex, and the subsequent O2 − production [2,6]
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