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- Title
Pioglitazone-incorporated microspheres targeting macrophage polarization alleviates cardiac dysfunction after myocardial infarction.
- Authors
Konegawa, Yasushi; Kuwahara, Toshie; Jo, Jun-Ichiro; Murata, Kozue; Takeda, Takahide; Ikeda, Tadashi; Minatoya, Kenji; Masumoto, Hidetoshi; Tabata, Yasuhiko
- Abstract
Open in new tab Download slide OBJECTIVES Excessive and chronic inflammation after a myocardial infarction (MI) is associated with left ventricular remodelling and impaired cardiac function. Among inflammatory cells, macrophages play a critical role in polarizing proinflammatory M1 or the reparative M2 subtype. Pioglitazone (PGZ) is reported to regulate macrophage polarization to the M2 subtype. Our goal was to validate the therapeutic effects and the mechanisms of PGZ utilizing a drug delivery system. METHODS Poly L-lactic-co-glycolic acid microspheres (MS) incorporating PGZ were prepared. To validate the therapeutic potential of PGZ-MS, Sprague-Dawley rats were subjected to permanent left coronary artery ligation to induce an MI. Placebo-MS (100 μg) or PGZ-MS (100 μg) was injected to the infarct region just after induction. Cardiac function and size were assessed by echocardiography. At 28 days after surgery, the rats were sacrificed, and the excised hearts were evaluated histologically. RESULTS Sustained release of PGZ from the PGZ-MS was confirmed in vitro. PGZ-MS significantly rehabilitated cardiac dysfunction after an MI (fractional shortening: MI vs MI+placebo-MS vs MI+PGZ-MS, 24.4 ± 1.1 vs 24.3 ± 1.6 vs 32.2 ± 1.4%; P = 0.0035) with reverse remodelling. Immunohistochemical analyses revealed that PGZ-MS enhanced macrophage polarization (ratio of M2 subtype: 0.39 ± 0.03 vs 0.42 ± 0.02 vs 0.54 ± 0.02; P = 0.0004) and attenuated apoptosis of cardiomyocytes in the ischaemic border zone. CONCLUSIONS We confirmed macrophage polarization by sustained release of PGZ, which resulted in amelioration of adverse left ventricular remodelling and cardiac dysfunction. Drug delivery system-based macrophage polarization might serve as a promising strategy in cardiac regenerative therapy for ischaemic heart disease. (241 words)
- Subjects
HEART diseases; MYOCARDIAL infarction; VENTRICULAR remodeling; MACROPHAGES; MYOCARDIAL reperfusion; HEART size; MACROPHAGE inflammatory proteins; TARGETED drug delivery
- Publication
European Journal of Cardio-Thoracic Surgery, 2022, Vol 62, Issue 5, p1
- ISSN
1010-7940
- Publication type
Article
- DOI
10.1093/ejcts/ezac414