Obesity and hypoxia have differential effects on myocardial innervation in the right ventricle of the male mouse heart.

Abstract

Obesity, along with hypoxia, is known to be a risk factor for pulmonary hypertension (PH), which can lead to right ventricular hypertrophy and eventually heart failure. Both obesity and PH influence the autonomic nervous system (ANS), potentially aggravating changes in the right ventricle (RV). This study investigates the combined effects of obesity and hypoxia on the autonomic innervation of the RV in a mouse model. Male C57BL/6N mice were subjected to a control diet (CD) or a high-fat diet (HFD) for 30 weeks, with subsets of the mice exposed to chronic normobaric hypoxia (13% O₂) during the final 3 weeks. Light and electron microscopic stereology was used to quantify various parameters of nerve fibres innervating the RV myocardium. HFD-induced obesity significantly increased the total length of nerve fibres and axons in the RV under normoxic conditions, indicating hyperinnervation. Quantitatively, the length density of nerve fibres per unit volume of RV (unit: x10^-3 µm^-2) was similar in CD (0.158 ± 0.04), CD-Hyp (0.176 ± 0.06) and HFD-Hyp (0.147 ± 0.05). In contrast, in HFD the length density of nerve fibres showed higher values 0.206 ± 0.054. The total length of nerve fibres increased by 67% from 2.61 m ± 0.77 m in CD to 4.37 m ± 1.51 m in HFD. The total length of axons increased by 80% from 8.87 m ± 2.75 m to 15.95 m ± 4.62 m. However, when obesity was combined with hypoxia, the total axon length was significantly reduced by 27% in HFD-Hyp compared with HFD. In addition, the mean number of axon profiles per nerve fibre profile decreased from 3.44 ± 0.68 in HFD to 2.95 ± 0.43 in HFD-Hyp. Interestingly, chronic hypoxia alone did not significantly alter RV innervation but led to RV hypertrophy, independent of the diet. The attenuation of obesity-induced hyperinnervation by hypoxia suggests a complex and potentially antagonistic interaction between these conditions. In conclusion, obesity induced by a HFD caused hyperinnervation of the RV, whereas chronic hypoxia alone did not significantly alter RV innervation. Surprisingly, chronic hypoxia attenuated the obesity-induced changes in RV innervation. These findings indicate that the effects of obesity and hypoxia-induced PH on RV innervation are distinct and potentially antagonistic.