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. 2021 Apr;21(4):331.
doi: 10.3892/etm.2021.9762. Epub 2021 Feb 8.

Pemafibrate suppresses oxidative stress and apoptosis under cardiomyocyte ischemia-reperfusion injury in type 1 diabetes mellitus

Wei Li  1 , Jianxin Xu  1 , Xin Guo  1 , Xinhua Xia  2 , Yanling Sun  2
Affiliations

Pemafibrate suppresses oxidative stress and apoptosis under cardiomyocyte ischemia-reperfusion injury in type 1 diabetes mellitus

Wei Li et al. Exp Ther Med. 2021 Apr.

Abstract

Diabetes mellitus accelerates the hyperglycemia susceptibility-induced injury to cardiac cells. The activation of peroxisome proliferator-activated receptor α (PPARα) decreases ischemia-reperfusion (IR) injury in animals without diabetes. Therefore, the present study hypothesized that pemafibrate may exert a protective effect on the myocardium in vivo and in vitro. A type 1 diabetes mellitus (T1DM) rat model and H9c2 cells exposed to high glucose under hypoxia and reoxygenation treatments were used in the present study. The rat model and the cells were subsequently treated with pemafibrate. In the T1DM rat model, pemafibrate enhanced the expression of PPARα in the diabetic-myocardial ischemia-reperfusion injury (D-IRI) group compared with the D-IRI group. The infarct size in the D-IRI group was reduced following pemafibrate treatment relative to the untreated group. The disruption of the mitochondrial structure and myofibrils in the D-IRI group was partially recovered by pemafibrate. In addition, to evaluate the mechanism of action of pemafibrate in the treatment of diabetic myocardial IR injury, an in vitro model was established. PPARα protein expression levels were reduced in the high glucose and hypoxia/reoxygenation (H/R) groups compared with that in the control or high glucose-treated groups. Pemafibrate treatment significantly enhanced the ATP and superoxide dismutase levels, and reduced the mitochondrial reactive oxygen species and malondialdehyde levels compared with the high glucose combined with H/R group. Furthermore, pemafibrate inhibited the expression of cytochrome c and cleaved-caspase-3, indicating its involvement in the regulation of mitochondrial apoptosis. Pemafibrate also reduced the expression of nuclear factor-κB (NF-κB), the activation of which reversed the protective effects of pemafibrate on diabetic myocardial IR injury in vitro. Taken together, these results suggested that pemafibrate may activate PPARα to protect the T1DM rat myocardium against IR injury through inhibition of NF-κB signaling.

Keywords: apoptosis; diabetes; myocardial ischemia-reperfusion injury; oxidative stress; peroxisome proliferator-activated receptor α.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Effects of pemafibrate on the extent of myocardial infarction and myocardial damage. (A and B) TTC staining of D-IRI induced infarction. (C) Immunohistochemistry for PPARα expression in cardiac tissues. Magnification, x200. (D) The ultrastructure of myocardial tissue from the D-IRI and D-IRI + pemafibrate groups revealed disrupted myofibrils (black arrowhead), rounded mitochondria with increased distance between cristae (small black arrow), electron-dense particles (red arrow), rupturing of the inner membranes resulting in protrusions from the mitochondria (thick black arrow), rupturing of the inner and outer membranes (red arrow head), normal mitochondria (blue arrow) and normal myofibrils (blue arrowhead). Scale bar, 100 µm. ***P<0.001 vs. D-IRI. D-IRI, diabetic-myocardial ischemia reperfusion injury; PPARα, peroxisome proliferator-activated receptor α; TTC, 2,3,5-triphenyltetrazolium chloride.
Figure 2
Figure 2
Pemafibrate reduces mitochondrial dysfunction in H9c2 cells following H/R. (A) Protein expression levels of PPARα under HG or HG + H/R conditions were detected by western blotting. **P<0.01 vs. control; #P<0.05 vs. HG. (B-E) Relative levels of (B) ATP, (C) mtROS, (D) MDA and (E) SOD were determined using commercial assay kits. ***P<0.001 vs. control; ##P<0.01, ###P<0.001 vs. HG + H/R. HG, high glucose; H/R, hypoxia/reperfusion; MDA, malondialdehyde; mtROS, mitochondrial reactive oxygen species; PPARα, peroxisome proliferator-activated receptor α; SOD, superoxide dismutase.
Figure 3
Figure 3
Pemafibrate inhibits mitochondria-dependent apoptosis in H9c2 cells exposed to high glucose conditions following H/R. (A) Flow cytometry was performed to detect and (B) quantify apoptotic cells using FITC-Annexin V and propidium iodide staining. (C) The expression levels of apoptosis-related proteins were evaluated using western blotting. **P<0.01, ***P<0.001 vs. control; #P<0.05, ###P<0.001 vs. HG + H/R. H/R, hypoxia/reperfusion; HG, high glucose; Cyt-c, cytochrome c.
Figure 4
Figure 4
The biological effects of pemafibrate treatment may be mediated by NF-κB signaling. (A) Protein expression levels of NF-κB were detected by western blotting. ***P<0.001 vs. control; ###P<0.001 vs. HG + H/R. (B) NF-κB expression was evaluated by reverse transcription-quantitative PCR following transfection. ***P<0.001 vs. NC. (C) Relative levels of ATP were detected using commercial kits. (D) The expression levels of apoptosis-related proteins were assessed by western blotting. **P<0.01, ***P<0.001 vs. control; #P<0.05, ###P<0.001 vs. HG + H/R; ΔΔP<0.01 vs. pemafibrate-treated HG + H/R; $$P<0.01 vs. pemafibrate-treated HG + I/R negative control. HG, high glucose; H/R, hypoxia/reperfusion; Cyt-c, cytochrome c; NF-κB, nuclear factor-κΒ; NC, negative control.
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