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. 2006 Nov-Dec;12(11-12):275-83.
doi: 10.2119/2006–00039.Gu.

Neovascularization of ischemic myocardium by newly isolated tannins prevents cardiomyocyte apoptosis and improves cardiac function

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Neovascularization of ischemic myocardium by newly isolated tannins prevents cardiomyocyte apoptosis and improves cardiac function

Xuemei Gu et al. Mol Med. 2006 Nov-Dec.

Retraction in

  • Notice of retraction.
    [No authors listed] [No authors listed] Mol Med. 2009 Sep-Oct;15(9-10):359. doi: 10.2119/molmed.2009.00039.Retraction. Mol Med. 2009. PMID: 19750127 Free PMC article. No abstract available.

Abstract

During remodeling progress post myocardial infarction, the contribution of neoangiogenesis to the infarct-bed capillary is insufficient to support the greater demands of the hypertrophied but viable myocardium resulting in further ischemic injury to the viable cardiomyocytes at risk. Here we reported the bio-assay-guided identification and isolation of angiogenic tannins (angio-T) from Geum japonicum that induced rapid revascularization of infarcted myocardium and promoted survival potential of the viable cardiomyocytes at risk after myocardial infarction. Our results demonstrated that angio-T displayed potent dual effects on up-regulating expression of angiogenic factors, which would contribute to the early revascularization and protection of the cardiomyocytes against further ischemic injury, and inducing antiapoptotic protein expression, which inhibited apoptotic death of cardiomyocytes in the infarcted hearts and limited infarct size. Echocardiographic studies demonstrated that angio-T-induced therapeutic effects on acute infarcted myocardium were accompanied by significant functional improvement by 2 days after infarction. This improvement was sustained for 14 days. These therapeutic properties of angio-T to induce early reconstitution of a blood supply network, prevent apoptotic death of cardiomyocytes at risk, and improve heart function post infarction appear entirely novel and may provide a new dimension for therapeutic angiogenesis medicine for the treatment of ischemic heart diseases.

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Figures

Figure 1
Figure 1
Isolation of the active compounds by bio-assay-guided fractionation strategy. (A) It was shown that the n-butanol fraction displayed a dose-dependent and the highest activities in enhancing the proliferation of human coronary artery endothelial cells (HCAECs). (B) Among the 7 separated fractions from n-Butanol extract, fraction 3 displayed most potent and dose-response effect on promoting the proliferation of HCAECs in vitro.
Figure 2
Figure 2
Early neovascularization of the infarcted myocardium following angio-T treatment. (A) Two days after LAD ligation and angio-T injection, numerous newly-formed vessels, some of which were filled with blood cells (red arrowheads) and some of which displayed as a lumen-like structure without filling of blood cells (blue arrowheads), were found in the whole infarct zone. (B) In contrast, only a few vessels with inflammatory cell infiltration were observed in the whole infarct zone in the control hearts on day 2 post MI. (C) Seven days after LAD ligation and angio-T injection, many functional vessels filled with blood cells were observed in the whole infarct areas. (D) The main feature was fibrous tissue replacement of the infarcted myocardium with only a few blood vessels in non-treated hearts on 7-day post-infarction. (E&F) RT-PCR and Western blot analysis demonstrated significantly up-regulated gene expressions of VEGFb and VEGFc in the angio-T treated heart tissues compared with their expressions in non-treated control myocardium.
Figure 3
Figure 3
Gene expression profiling analysis of signal transduction pathway. (A) 15 genes were found to be up-regulated in the angio-T treated heart tissues compared with those in non-treated control myocardium. Each circle marked by number 1–15 stands for: BAX, BCL2, BMP4, CDKN1b, FASN, CCL20, CDKN2a, ICAM1, IL4R, IRF1, MDM2, ODC1, PRKCE, TRIM25 and GADD45a respectively (Table 2). (B) RT-PCR analysis demonstrated significantly up-regulated gene expression of IL4R and IRF1 in the angio-T treated heart tissues.
Figure 4
Figure 4
Angio-T-enhanced survival potential and reduction of infarct size. (A) Seven days after LAD ligation, the irregular myocytes at the peri-infarct rim had more apoptotic nuclei in the control (a). In contrast, the myocytes were regular and few apoptotic nuclei were evident in the peri-infarct rim of rats in angio-T-treated hearts. (B) Western Blot analysis showed the increased gene expressions of phospho-Akt1 and Bcl2 respectively upon angio-T treatment compared with their expressions in control hearts. (C) The trichrome staining of the rat myocardium at 2-week post infarct. There was extensive loss of anterior free wall myocardial mass, with collagen deposition and scar formation extending almost through the entire free wall of left ventricular (a). In contrast, trichrome stain of rat myocardium at 2-week post infarction in angio-T treated rats showed significantly reduced infarct size and increased mass of viable myocardium within the anterior wall (b).
Figure 5
Figure 5
The effects of the angio-T treatment on myocardial function of rats following MI. LVEF in angio-T treated hearts had significantly improved compared with that in control hearts on day 2 (P < 0.001) and day 14 (P < 0.001) post infarction. FS in angio-T treated hearts was significantly higher than that in control group on day 2 (P < 0.05) and day 14 (P < 0.001) post infarction.

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