Cristhian Gutierrez Huerta (Medical College of Wisconsin), Shelby Hader (Medical College of Wisconsin), Jason Beare (University of Louisville), Evan Tracy (University of Louisville), Katherine Astbury (Medical College of Wisconsin), Elizabeth Jacobs (Medical College of Wisconsin, Medical College of Wisconsin), Amanda LeBlanc (University of Louisville), David Gutterman (Medical College of Wisconsin, Medical College of Wisconsin), Andreas Beyer (Medical College of Wisconsin)
Introduction: Advanced age is a well-documented risk factor for coronary microvascular dysfunction. Recent evidence has underscored that advanced age is associated with a shift toward greater mitochondrial fission rather than mitochondrial fusion. Therefore, understanding key regulators of the balance of mitochondrial fission/fusion may help to identify the contribution of mitochondrial dynamics on microvascular endothelial function. DRP1 is a pro-fission factor that has been linked to several disease manifestations including advanced age and cardiovascular disease (CVD).
Methods: Coronary arteries were obtained from young control rats (YC, 15-20 weeks) and old control rats (OC, 95-100 weeks) and expression of DRP1 was assessed by immunofluorescence (IF). A novel rat model crossing flox-stop DRP1-GFP rats and VECAD-Cre expressing rats was generated to assess the vascular and cardiac effects of endothelial-specific DRP1 overexpression. Endothelial vascular function was determined by endothelial-dependent flow-mediated dilation while cardiac function was determined by echocardiography at 20 weeks old and compared to wildtype control group.
Results: Data from IF comparing coronary arteries from YC and OC show that OC had higher DRP1 expression compared to YC (1.42 to 1.00, p=0.01). Max dilation measurements, taken at 20-weeks of age, showed that DRP1-overexpressing rats was decreased when compared to wildtype (WT) control rats (31.4 to 60.1, p=0.009). Echocardiography revealed that DRP1-overexpressing rats showed a trend towards a decrease in coronary flow reserve and increased HR in response to a dobutamine stressor when compared to WT. Ejection fraction between the two groups remained largely preserved.
Conclusion: Our data demonstrate that there may be a critical role for DRP1 within in vitro vasodilation that mimics a CVD pro-fission phenotype. Future studies will be performed to further evaluate the role of DRP1 in response to other stressors well-established in age-dependent CVD such as hypertension.
Support or Funding Information
Funded by R01-HL116530 (ERJ), R01-AG053585-05 (AJL), R01-HL133029-05 (AMB), R01-HL157025-01 (DDG), and R01-HL135901-04 (DDG)
lt;pgt;Funded by R01-HL116530 (ERJ), R01-AG053585-05 (AJL), R01-HL133029-05 (AMB), R01-HL157025-01 (DDG), and R01-HL135901-04 (DDG)lt;/pgt;
Overexpression of Drp1 is associated with cardiac and microvascular dysfunction
