Phenotypic differences of chronic angiotensin II/phenylephrine infusion in C57BL/6J and C57BL/6N mouse strains - 21/05/25
, Iman Momken 2, Mathias Mericskay 1
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Summary |
Introduction |
Hypertension is present in 75% of patients suffering heart failure with preserved ejection fraction (HFpEF) patients while obesity is present in average in only 30–40%. Angiotensin II/phenylephrine (ANGII/PE) infusion in mice is a new model of HFpEF without obesity [1]. The C57BL/6J (B6J) and C57BL/6N (B6N) inbred substrains are frequently used to study pathological models. The metabolic phenotypic differences between B6J and BL6N are considered to be influenced by the nicotinamide nucleotide transhydrogenase (Nnt) gene, which is found only in B6J. Nnt is a key antioxidative enzyme based on its ability to regenerate NADPH from NADH.
Objective |
We aim to compare the effects of ANG II/PE infusion on B6J and B6N mice.
Method |
Male mice (8 week-old) were implanted with an osmotic minipump to allow continuous infusion of ANG II/PE for 21 days. Echocardiography was performed at 19/20 days. Cardiac hypertrophy and fibrosis were evaluated by histological methods and by qRT-PCR and Western blot. Mitochondrial respiration was assessed by oxygrqphy and NAD was quantified by the alcohol dehydrogenase cycling assay.
Results |
Radial fractional shortening was preserved in B6J-ANGII/PE and LVEF (B-mode) was moderately reduced to 43 vs. 61% in control (saline) group, while both parameters were severely reduced in B6N mice. AngII/PE significantly increased E/A ratio in B6J that exhibited concentric hypertrophy, whereas B6N mice exhibited eccentric hypertrophy and A wave was not detected. Lung weight to tibia length ratio was increased in both strains. B6N mice showed more severe cardiac fibrosis and hypertrophy. Increased protein expression of Pparg coactivator 1 alpha (PGC-1α) and Sirtuin1 was observed with AngII/PE in B6N mice only. There was no significant difference in mitochondrial oxidative capacity and NAD levels between B6N and B6J mice and no impact of the treatment.
Conclusion |
With AngII/PE infusion, B6J mice presented features of HF with mid-range EF while B6N mice developed HF with reduced ejection fraction (HFrEF). This new model provides an angle to study the divergent pathophysiological pathways of HFpEF vs HFrEF in the context of hypertension. Our future studies will also aim to identify the different molecular mechanisms of B6J and B6N mice under thispathological stimulation and explore biological sex differences.
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Vol 118 - N° 6-7S1
P. S207 - juin 2025 Regresar al número
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