TT-10–loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarction
Wangping Chen, … , Jinfu Yang, Jianyi Zhang
Wangping Chen, … , Jinfu Yang, Jianyi Zhang
Published October 22, 2021
Citation Information: JCI Insight. 2021;6(20):e151987. https://doi.org/10.1172/jci.insight.151987.
View: Text | PDF
Research Article Cardiology Therapeutics

TT-10–loaded nanoparticles promote cardiomyocyte proliferation and cardiac repair in a mouse model of myocardial infarction

Abstract

The meager regenerative capacity of adult mammalian hearts appears to be driven by the proliferation of endogenous cardiomyocytes; thus, strategies targeting mechanisms of cardiomyocyte cell cycle regulation, such as the Hippo/Yes-associated protein (Hippo/Yap) pathway, could lead to the development of promising therapies for heart disease. The pharmacological product TT-10 increases cardiomyocyte proliferation by upregulating nuclear Yap levels. When intraperitoneal injections of TT-10 were administered to infarcted mouse hearts, the treatment promoted cardiomyocyte proliferation and was associated with declines in infarct size 1 week after administration, but cardiac function worsened at later time points. Here, we investigated whether encapsulating TT-10 into poly-lactic-co-glycolic acid nanoparticles (NPs) before administration could extend the duration of TT-10 delivery and improve the potency of TT-10 for myocardial repair. TT-10 was released from the TT-10–loaded NPs for up to 4 weeks in vitro, and intramyocardial injections of TT-10–delivered NPs stably improved cardiac function from week 1 to week 4 after administration to infarcted mouse hearts. TT-10–delivered NP treatment was also associated with significantly smaller infarcts at week 4, with increases in cardiomyocyte proliferation and nuclear Yap abundance and with declines in cardiomyocyte apoptosis. Thus, NP-mediated delivery appears to enhance both the potency and durability of TT-10 treatment for myocardial repair.

Authors

Wangping Chen, Danielle Pretorius, Yang Zhou, Yuji Nakada, Jinfu Yang, Jianyi Zhang

×

Figure 4

Intramyocardial injections of TT-10–NPs improved recovery from MI in mice.

Options: View larger image (or click on image) Download as PowerPoint
Intramyocardial injections of TT-10–NPs improved recovery from MI in mic...
MI was induced in mice, and then the animals were treated with DPBS, empty PLGA NPs (Empty-NP), TT-10 solution (TT-10–SOL), or with TT-10–loaded PLGA NPs (TT-10–NP). A fifth group of animals (the sham group) underwent all surgical procedures for MI induction except arterial ligation. (A) Echocardiographic assessments of (B) left ventricular ejection fraction (LVEF), (C) fractional shortening (LVFS), (D) end-systolic diameter (LVESD), and (E) end-diastolic diameter (LVEDD) were conducted before MI induction (pre-s) and 1 and 4 weeks afterward. Representative images in A were collected at week 4. (F–H) Animals were sacrificed at week 4, and hearts were explanted. (F) Heart sections were stained with Picrosirius Red and Fast Green to identify regions of infarcted (red) and noninfarcted (green) tissue. Scale bar: 1 mm. (G) Then, infarct sizes were quantified as the ratio of the scar area to the total left ventricular surface area and expressed as a percentage. (H) Myocardial hypertrophy was evaluated as the ratio of the weight of the whole heart to the animal’s bodyweight (HW/BW). (B–E) n = 7–9 animals per group. *P < 0.01 vs. DPBS, †P < 0.05 vs. DPBS, #P < 0.01 vs. Empty-NP, &P < 0.01 vs. TT-10–SOL; 2-way ANOVA with Tukey’s multiple comparisons test. (G and H) n = 7–9 animals per group; ¥P < 0.01 vs. sham, †P < 0.05 vs. sham, *P < 0.01 vs. MI, #P < 0.01 vs. Empty-NP, &P < 0.01 vs. TT-10–SOL; 1-way ANOVA with Tukey’s multiple comparisons test.