Cardiomyocyte-targeted HIF-1α gene therapy inhibits cardiomyocyte apoptosis and cardiac allograft vasculopathy in the rat

Keränen, Mikko; Nykänen, Antti; Krebs, R.; Pajusola, Katri; Tuuminen, Raimo; Alitalo, Kari; Lemström, Karl

doi:10.1016/j.healun.2010.05.021

Cited by 13 publications

(8 citation statements)

References 31 publications

(22 reference statements)

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“…Western blot analysis confirmed the specificity of a monoclonal mouse antihuman antibody against HIF‐1α, as it detected the expected 120 kDa band in nuclear protein extracted from Cos‐7 cells treated with CoCl 2 (Figure B). We have previously shown that this antibody also detects HIF‐1α protein produced after adeno‐associated virus‐mediated gene transfer of HIF‐1α into rat cardiomyocytes in vivo .…”

Section: Resultsmentioning

confidence: 99%

Differential Effects of Pharmacological HIF Preconditioning of Donors Versus Recipients in Rat Cardiac Allografts

Keränen

Tuuminen

Syrjälä

et al. 2013

American Journal of Transplantation

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Ischemia-reperfusion injury (IRI) induces hypoxiainducible factor-1 (HIF-1) in the myocardium, but the consequences remain elusive. We investigated HIF-1 activation during cold and warm ischemia and IRI in rat hearts and cardiac syngrafts. We also tested the effect of HIF-a stabilizing prolyl hydroxylase inhibitor (FG-4497) on IRI or allograft survival. Ex vivo ischemia of the heart increased HIF-1a expression in a time-and temperature-dependent fashion. Immunohistochemistry localized HIF-1a to all cardiac cell types. After reperfusion, HIF-1a immunoreactivity persisted in smooth muscle cells and cardiomyocytes in the areas with IRI. This was accompanied with a transient induction of protective HIF-1 downstream genes. Donor FG-4497 pretreatment for 4 h enhanced IRI in cardiac allografts as evidenced by an increase in cardiac troponin T release, cardiomyocyte apoptosis, and activation of innate immunity. Recipient FG-4497 pretreatment for 4 h decreased infiltration of ED1 + macrophages, and mildly improved the longterm allograft survival. In syngrafts donor FG-4497 pretreatment increased activation of innate immunity, but did not induce myocardial damage. We conclude that the HIF-1 pathway is activated in heart transplants. We suggest that pharmacological HIF-a preconditioning of cardiac allografts donors would not lead to clinical benefit, while in recipients it may result in antiinflammatory effects and prolonged allograft survival.

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Section: Resultsmentioning

confidence: 99%

Differential Effects of Pharmacological HIF Preconditioning of Donors Versus Recipients in Rat Cardiac Allografts

Keränen

Tuuminen

Syrjälä

et al. 2013

American Journal of Transplantation

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“…Since natural compounds may promote VEGF/antioxidant signaling and inhibit the onset of apoptosis in hearts undergoing I/R 48 , we assessed the myocardial levels of cleaved caspase-3, an established pro-apoptotic factor. The levels of cleaved caspase-3 were significantly lower in P-BBG hearts, even though the myocardial protein expression of HIF-1α, a transcriptional factor involved in the induction of VEGF expression 49 as well as in the inhibition of apoptosis 50 , was similar in both experimental groups. These results are in agreement with our previous in vitro study 22 and suggest the activation of different signaling pathways by BBG.…”

Section: Discussionmentioning

confidence: 86%

Long-term Intake of Pasta Containing Barley (1–3)Beta-D-Glucan Increases Neovascularization-mediated Cardioprotection through Endothelial Upregulation of Vascular Endothelial Growth Factor and Parkin

Casieri

Matteucci

Cavallini

et al. 2017

Sci Rep

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Barley (1–3)β-D-Glucan (BBG) enhances angiogenesis. Since pasta is very effective in providing a BBG-enriched diet, we hypothesized that the intake of pasta containing 3% BBG (P-BBG) induces neovascularization-mediated cardioprotection. Healthy adult male C57BL/6 mice fed P-BBG (n = 15) or wheat pasta (Control, n = 15) for five-weeks showed normal glucose tolerance and cardiac function. With a food intake similar to the Control, P-BBG mice showed a 109% survival rate (P < 0.01 vs. Control) after cardiac ischemia (30 min)/reperfusion (60 min) injury. Left ventricular (LV) anion superoxide production and infarct size in P-BBG mice were reduced by 62 and 35% (P < 0.0001 vs. Control), respectively. The capillary and arteriolar density of P-BBG hearts were respectively increased by 12 and 18% (P < 0.05 vs. Control). Compared to the Control group, the VEGF expression in P-BBG hearts was increased by 87.7% (P < 0.05); while, the p53 and Parkin expression was significantly increased by 125% and cleaved caspase-3 levels were reduced by 33% in P-BBG mice. In vitro, BBG was required to induce VEGF, p53 and Parkin expression in human umbelical vascular endothelial cells. Moreover, the BBG-induced Parkin expression was not affected by pifithrin-α (10 uM/7days), a p53 inhibitor. In conclusion, long-term dietary supplementation with P-BBG confers post-ischemic cardioprotection through endothelial upregulation of VEGF and Parkin.

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“…[158][159][160] Stem cells overexpressing HIF-1a showed improved survival and angiogenic response posttransplantation. On the same note, mutagenesis of HIF-1a produced by substitution of alanine (Ala) for proline (Pro) at position 564 and asparagine (Asp) at position 803 was performed to reduce its degradation and enhance its biological half-life.…”

Section: A Hypoxic Preconditioning Of Stem Cellsmentioning

confidence: 99%

Preconditioning Approach in Stem Cell Therapy for the Treatment of Infarcted Heart

Haider

Ashraf

2012

Progress in Molecular Biology and Translational Science

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Cardiomyocyte-targeted HIF-1α gene therapy inhibits cardiomyocyte apoptosis and cardiac allograft vasculopathy in the rat

Cited by 13 publications

References 31 publications

Differential Effects of Pharmacological HIF Preconditioning of Donors Versus Recipients in Rat Cardiac Allografts

Differential Effects of Pharmacological HIF Preconditioning of Donors Versus Recipients in Rat Cardiac Allografts

Long-term Intake of Pasta Containing Barley (1–3)Beta-D-Glucan Increases Neovascularization-mediated Cardioprotection through Endothelial Upregulation of Vascular Endothelial Growth Factor and Parkin

Preconditioning Approach in Stem Cell Therapy for the Treatment of Infarcted Heart

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