NESS - Drug-Induced Modified Extracellular Vesicles (EVs) are More Potent than Unmodified Extracellular Vesicles In The Preservation of Cardiac Function In The Murine Myocardial Infarction Model

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Drug-Induced Modified Extracellular Vesicles (EVs) are More Potent than Unmodified Extracellular Vesicles In The Preservation of Cardiac Function In The Murine Myocardial Infarction Model
Nicole A. Taylor^*¹, Andrea Watters¹, Mahesh Thirunavukkarasu¹, John A. Palesty², Nilanjana Maulik¹
¹Department of Surgery, University of Connecticut Health, Farmington, CT; ²Stanley J. Dudrick Department of Surgery, St. Mary's Hospital, Waterbury, CT

Background: We have previously demonstrated that inhibiting prolyl hydroxylases (PHD1, PHD2, PHD3) led to increased angiogenesis and preserved cardiac function in murine myocardial infarction (MI) and hindlimb ischemia models. Dimethyloxalylglycine (DMOG) is a well-known prolyl hydroxylase inhibitor. Sometimes, drug resistance is a major clinical problem that leads to treatment failure. Therefore, we sought to compare the effect on cardiac function using DMOG versus extracellular vesicles (EVs) isolated from DMOG-treated mice in the murine MI model.
Study Design: Extracellular vesicle isolation: CD1 mice (8-12 weeks old) pre-treated with two doses of either PBS or DMOG (400mg/kg body weight) were subjected to left anterior descending coronary artery ligation (MI) or thoracotomy without coronary artery ligation (Sham). Plasma was collected 8 hours post-MI to isolate EVs from three groups: Sham (shamEVs), MI (MIEVs), and DMOG MI (DMOGMIEVs). All mice underwent preoperative echocardiogram. The mice were divided into six experimental groups for the comparison study: (1) Sham, (2) CMI, (3) DMOG+MI, (4) MI+ShamEVs, (5) MI+MIEVs (6) MI+DMOGMIEVs. In the groups, EVs were administered (4 sites, 25�L each) into the myocardium at the area of risk. Echocardiography was performed 4-weeks after surgery, and cardiac functions were compared between DMOG and DMOG-modified EV treatments.
Results: Echocardiogram demonstrated improved ejection fraction in the MI^DMOGEV group (58.01�4.46,%, n=5) compared to MI^shamEVs(28.81�3.52, %, n=5, p=0.0009), MI^MIEV(23.21�3.07, %, p=0.0002,n=5), and DMOG+MI (43.53�0.68, %, p=0.0124,n=5). The MI^DMOGEV group (30.49�3.03, %, n=5) also demonstrated improved fractional shortening compared to MI^shamEV(13.24�1.86, %,n=5, p=0.0013), MI^MIEV(10.53�1.47, %,p=0.0003, n=5), and DMOG+MI (21.16�0.43, %,p=0.0003, n=5). Also, left ventricular inner diameter at systole was found to be significant in MI^DMOGEV group (2.762�0.2678mm vs 3.685�0.2939 mm, p=0.0252, n=5 ) compared to MI^MIEV group. Stroke volume (38.96�2.502, ?l vs 17.03�2.75?l, p=0.0031, n=5 ) and left ventricular volume at systole (30.43�6.70, ?l vs. 59.83�10.68?l, p=0.0139, n=5 ) also showed similar results in the MI^DMOGEV group compared to MI^MIEV group.
Conclusion: Engineered EVs obtained from mice pre-treated with DMOG before MI demonstrated preserved cardiac function compared to DMOG treatment in MI. Using drug-modified EVs can minimize systemic toxicity and deliver cargo' to the cells in a real-time fashion. This study provides new avenues for developing drug-induced modified EVs as therapeutic strategies in the field of cardiac disease.

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