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IL-10 provides cardioprotection in diabetic myocardial infarction via upregulation of Heme clearance pathways
Rajesh Gupta, … , Jiang Tian, Raj Kishore
Rajesh Gupta, … , Jiang Tian, Raj Kishore
Published September 3, 2020
Citation Information: JCI Insight. 2020;5(17):e133050. https://doi.org/10.1172/jci.insight.133050.
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Research Article Cardiology Therapeutics

IL-10 provides cardioprotection in diabetic myocardial infarction via upregulation of Heme clearance pathways

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Abstract

Diabetes is a risk factor for myocardial infarction, and outcomes after myocardial infarction are worse among diabetics compared with nondiabetics. Diabetes is associated with impaired Heme clearance. Here, we determined whether heme toxicity and impaired heme clearance contribute to diabetic myocardial infarction injury and assessed IL-10 as a therapeutic agent for diabetic myocardial infarction. Plasma-free hemoglobin was significantly elevated in diabetic mice compared with nondiabetic mice after myocardial infarction. Infarct size had strong correlation to the level of plasma-free hemoglobin. Hemoglobin and reactive iron deposition within the infarct zone were also demonstrated in diabetic MI. IL-10 significantly reduced infarct size and improved cardiac function in diabetic mice. Moreover, IL-10 improved capillary density, reduced apoptosis, and decreased inflammation in the border zone of the infarcted hearts, findings that were partially inhibited by Tin protoporphyrin (a heme oxygenase-1 inhibitor). IL-10 upregulated CD163, the hemoglobin:haptoglobin scavenger receptor, and heme oxygenase-1 in THP-1–derived and primary human CD14+ macrophages. IL-10 significantly protected against ischemic injury when HL-1 cardiomyocytes were cotreated with hemoglobin. Together, our findings indicate that IL-10 is cardioprotective in diabetic myocardial infarction via upregulation of heme clearance pathways. These findings implicate heme clearance as a potentially novel therapeutic direction for diabetic myocardial infarction.

Authors

Rajesh Gupta, Lijun Liu, Xiaolu Zhang, Xiaoming Fan, Prasanna Krishnamurthy, Suresh Verma, Jörn Tongers, Sol Misener, Nikita Ashcherkin, Hongliu Sun, Jiang Tian, Raj Kishore

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Figure 4

IL-10 reduced cardiomyocyte apoptosis and increased capillary density in the infarct border zone after MI in the diabetic mice.

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IL-10 reduced cardiomyocyte apoptosis and increased capillary density in...
(A) Representative images of TUNEL assay (total original magnification, ×400). Arrows indicate TUNEL+ cells. Cardiomyocyte apoptosis was determined by the ratio of TUNEL+ cells to total cells. (B) Quantitative data of TUNEL assay. One-way ANOVA, followed by Tukey’s test; n = 3, *P < 0.05 vs. sham, #P < 0.05 vs. MI + vehicle. (C) Representative images of lectin-positive cells in hearts (total original magnification, ×100). Mice were injected with BS-1 lectin via the tail vein at least 10 minutes before sacrifice, and tissue sections were stained for lectin expression. (D) Quantitative data on capillary densities of infract border zone on day 3 after MI. One-way ANOVA, followed by Tukey’s test; n = 3, *P < 0.05 vs. sham, #P < 0.05 vs. MI + vehicle.

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