440Neuro-cardiac communication in the acute and chronic regulation of heart function and structure occurs through direct intercellular coupling
Authors: M Mongillo, V Prando, N Pianca, F Da Broi, A P Plazzo, M Franzoso, A P Di Bona, C Basso, T Zaglia
Journal: Cardiovascular Research (2018)

Background: Moderate-intensity exercise (MIE) is recommended as a primary prevention for cardiovascular diseases in type-2 diabetic individuals.Unfortunately, current clinical guideline does not specify which exercise intensity is effective to prevent microvascular remodeling for diabetic individuals with or without pre-existing cardiac dysfunction.Hence, controversial effects of MIE were reported.Therefore, the impact of MIE on diabetic individuals with various prognoses remains to be established.Purpose: To assess the effect of MIE on collateral growth and microRNA-126/VEGF pathway in db/db mice with or without established cardiac dysfunction, independently.Methods: 8-week old diabetic db/db mice without cardiac dysfunction (Pre-CD) or 16-week old db/db mice with established cardiac dysfunction (Post-CD) were subjected to MIE or no exercise.Age-matched non-diabetic db/þ mice with normal cardiac function were used as controls.Mice were subjected to exercise for 5 consecutive days a week for 8 weeks.Each daily exercise consisted of 10 bouts of 5 minutes run interspersed by 2 minutes of rest.Cardiac function was measured at baseline and endpoint using echocardiography.Heart tissues were harvested to assess myocardial angiogenic properties by quantifying (i) arterioles density and functional capillaries using immunohistochemistry, (ii) microRNA-126 using real-time PCR and (iii) its indirect target vascular endothelial growth factor (VEGF) using western blot.Results: Body weight and HbA1c remain unaltered in all mice.Ejection fraction and E/A ratio were impaired in Pre-and Post-CD diabetic controls at the end of 8-week study.Arteriole density and functional capillaries were significantly reduced in both groups of diabetic control, indicating microvascular rarefaction and poor myocardial perfusion.These structural changes were associated with down-regulations of pro-angiogenic factors -microRNA-126 and VEGF protein.Interestingly, MIE prevented deterioration of cardiac function in Pre-CD mice but MIE did not attenuate cardiac dysfunction in Post-CD mice.Amelioration of cardiac function in Pre-CD mice was associated with increased microvascular density, suggesting enhanced myocardial perfusion.This structural adaptation was also partly contributed by preserved microRNA-126 expression and VEGF protein, suggesting a normal angiogenic property.In contrast, microRNA-126 and VEGF level was not restored by MIE, resulting in cardiac microangiopathy and cardiac dysfunction in Post-CD mice.Conclusion: Our data supports current clinical guidelines that MIE is effective as a primary prevention for cardiovascular disease, provided an early intervention is initiated in uncomplicated diabetic individuals.This data also provides a translational evidence for future clinical study that patient's prognosis should be taken into consideration in order to maximize the clinical benefits of MIE in diabetic patients.