Abstract P2151: A Novel, Micellized Naringenin Nanoparticle Rescues Hemodynamic Function Post-Myocardial Infarction Via MARK4 Inhibition
Circulation Research(2023)
Abstract
Impaired contractility and associated shock are significant contributors to morbidity after myocardial infarction (MI). Elevated MARK4 activity after MI impairs contractility by increasing α-tubulin detyrosination. As such, we developed a nanoparticle-based therapeutic strategy to enhance myocyte function with a small molecule MARK4 inhibitor (naringenin) and tested its ability to improve myocyte function in a rat model of MI. Naringenin was encapsulated in PEO-PCL to augment bioavailability. Adult Wistar rats underwent thoracotomy and were randomized to receive either: MI + myocardial injection of micellized naringenin (0.3 mg/kg) [MI-Nar], MI + empty micelle [MI-Mic], MI alone [MI-Untreated], or no MI [Sham]. MI was achieved with left anterior descending artery ligation. On pressure-volume hemodynamic assessment 24 hours post-thoracotomy, MI-Nar rats had higher ejection fractions than MI-Mic or MI-Untreated rats (63±3% v. 48±5% vs. 39±4%, p<0.05) and similar levels to Sham rats (61±1%, p=0.97). MI-Nar rats had greater stroke work, and lower end-diastolic pressure and tau than MI-Untreated rats (all p<0.05). Isolated myocytes from infarct border zones had increased contraction and relaxation velocity in MI-Nar versus MI-Untreated rats (both p<0.0001; Fig. 1A, B). Improved function was associated with decreased α-tubulin detyrosination in MI-Nar versus MI-Untreated rats on Western blot (p<0.05; Fig. 1C, D). These data support small molecule inhibition of MARK4 via micellized naringenin as a novel strategy to rescue hemodynamics post-MI by mitigating myocardial α-tubulin detyrosination and enhancing myocyte function.
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