Abstract
Background: Cardiac autonomic neuropathy (CAN) is a key component of diabetic heart disease (DHD) and a cardiovascular complication of Type 2 Diabetes Mellitus (T2DM) that is often underdiagnosed. A growing body of literature reported that T2DM is associated with tau-mediated neurodegeneration. Dysregulation of microRNA-138 (miR-138) has been associated with tau dysregulation. However, the mechanistic role of miR-138 in modulating tau driving CAN remains unknown.
Aims: To investigate the role of miR-138 in modulating tau expression driving CAN in T2DM. To explore the role of miR-138 in modulating coronary function in T2DM via CAN.
Methods: To evaluate the mechanistic role of miR-138, diabetic mice were treated with antimiR-138 and non-diabetic mice were treated with miR-138 mimic for 8 weeks. Echocardiography was performed to assess cardiac function during treatment. Immunohistochemistry and RT-PCR were performed to assess tau and autonomic nerve expression and miR-138 expression respectively. In vivo coronary microangiography and haemodynamic evaluation were performed to assess coronary function and baroreflex sensitivity respectively.
Results: This study revealed that tau expression in cardiac sympathetic nerves was significantly reduced in 16-week-old diabetic (DM) mice (0.017 ± 0.009 Tau/TH in DM vs 0.146 ± 0.039 tau/TH in non-DM; p<0.01) which showed early signs of CAN and preserved cardiac and coronary function. Anti-miR-138 treatment restored tau expression in sympathetic nerves in diabetes (0.192 ±0.029 tau/TH in DM (anti-miR-138) vs 0.017 ±0.009 tau/TH in DM; p<0.01). This restored the heart rate pattern of DM mice to that of non-DM mice and impeded cardiac remodelling. In contrast, miR-138 mimic treatment induced diastolic dysfunction and cardiac remodelling in non-DM mice despite no significant changes in tau expression in sympathetic nerves. Furthermore, miR-138 mimic treatment reduced baroreflex sensitivity, induced neovascularisation and impaired vasodilatory response of 100-150 μm coronary vessels to propranolol (1.00 ±4.08% in non-DM vs 14.30 ±4.52% in non-DM (mimic); p<0.05).
Conclusion: This study provides first evidence that tau dysregulation contributes to CAN which precedes changes to cardiac and coronary function in T2DM. This study also provides preliminary evidence that miR-138 potentially modulates tau in driving CAN, slowing down the progression of DHD. This provides a potential biomarker to help diagnose and manage CAN earlier.