Objectives: To assess the role of hypoxia-induced transcription factor (HIFs) and reactive oxygen
species (ROS) on disease progression in a hypertrophic cardiomyopathy mouse model.
Methods: Mice carrying the human Arg719Trp mutation in the α-cardiac myosin heavy chain gene
(αMHC719/+) were compared with wildtypes (WT). Myocardial wall thickness was measured on M-mode
in vivo echocardiographic imaging. RNA and protein expression of the myocardial HIF1α
as well as components of the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase
was assessed ex vivo by real-time polymerase chain reaction (RT-PCR) and by western
blot, respectively. ROS production was measured by electron paramagnetic resonance.
Results: αMHC719/+ mice developed hypertrophic cardiomyopathy. Myocardial HIF1α expression was increased
on both the RNA as well as the protein level in αMHC719/+ as compared with WT mice. There was an upregulation of p22phox, an essential component
of the NADPH-oxidase, on a protein but not on the RNA-level in αMHC719/+ as compared with WT mice (see [Table 1]). αMHC719/+ mice showed an increase in relative ROS- and superoxide-generation.
Table 1
Results
|
WT (N = 3–5)
|
αMHC719/+ (N = 3–5)
|
p-value
|
|
Abbreviations: HIF1α, hypoxia inducible factor 1α; LVWT, left ventricular wall thickness.
|
|
Data expressed in mean ± standard deviation.
|
|
LVWT (Echocardiography) (mm)
|
0.73 ± 0.05
|
1.13 ± 0.08
|
<0.001
|
|
Relative mRNA HIF1α (RT-PCR) (-fold)
|
1
|
2.6 ± 0.4
|
<0.01
|
|
Relative mRNA expression p22phox (RT-PCR) (-fold)
|
1
|
1.3 ± 0.7
|
NS
|
|
Relative protein expression HIF1α (Western blot) (-fold)
|
1
|
3.2 ± 0.4
|
<0.05
|
|
Relative protein expression p22phox (Western blot)(-fold)
|
1
|
5.4 ± 0.3
|
<0.05
|
Conclusion: Activation of HIFs and increased ROS production suggest the influence of inflammatory
pathways on pathogenesis in a murine HCM mouse model. These results might offer new
treatment targets in HCM.
