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.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call