Upregulation of Inflammatory Pathways in Mice with Hypertrophic Cardiomyopathy

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 (αMHC^719/+) 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: αMHC^719/+ mice developed hypertrophic cardiomyopathy. Myocardial HIF1α expression was increased on both the RNA as well as the protein level in αMHC^719/+ 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 αMHC^719/+ as compared with WT mice (see [Table 1]). αMHC^719/+ 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.

 

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