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Improving reconstituted HDL composition for efficient post-ischemic reduction of ischemia reperfusion injury.

Brulhart-Meynet MC, Braunersreuther V, Brinck J, Montecucco F, Prost JC, Thomas A, Galan K, Pelli G, Pedretti S, Vuilleumier N, Mach F, Lecour S, James RW, Frias MA - PLoS ONE (2015)

Bottom Line: Acute post-ischemic treatment with native HDL significantly reduced infarct size and cell death in the ex vivo, isolated heart (Langendorff) model and the in vivo model (-48%, p<0.01).This impact was comparable with the effects observed with native HDL.HDL afford protection against IRI in a clinically relevant model (post-ischemia). rHDL is significantly protective if supplemented with S1P.

View Article: PubMed Central - PubMed

Affiliation: Service of Endocrinology, Diabetology, Hypertension and Nutrition, Department of Internal Medicine, Faculty of Medicine, Geneva, Switzerland.

ABSTRACT

Background: New evidence shows that high density lipoproteins (HDL) have protective effects beyond their role in reverse cholesterol transport. Reconstituted HDL (rHDL) offer an attractive means of clinically exploiting these novel effects including cardioprotection against ischemia reperfusion injury (IRI). However, basic rHDL composition is limited to apolipoprotein AI (apoAI) and phospholipids; addition of bioactive compound may enhance its beneficial effects.

Objective: The aim of this study was to investigate the role of rHDL in post-ischemic model, and to analyze the potential impact of sphingosine-1-phosphate (S1P) in rHDL formulations.

Methods and results: The impact of HDL on IRI was investigated using complementary in vivo, ex vivo and in vitro IRI models. Acute post-ischemic treatment with native HDL significantly reduced infarct size and cell death in the ex vivo, isolated heart (Langendorff) model and the in vivo model (-48%, p<0.01). Treatment with rHDL of basic formulation (apoAI + phospholipids) had a non-significant impact on cell death in vitro and on the infarct size ex vivo and in vivo. In contrast, rHDL containing S1P had a highly significant, protective influence ex vivo, and in vivo (-50%, p<0.01). This impact was comparable with the effects observed with native HDL. Pro-survival signaling proteins, Akt, STAT3 and ERK1/2 were similarly activated by HDL and rHDL containing S1P both in vitro (isolated cardiomyocytes) and in vivo.

Conclusion: HDL afford protection against IRI in a clinically relevant model (post-ischemia). rHDL is significantly protective if supplemented with S1P. The protective impact of HDL appears to target directly the cardiomyocyte.

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Related in: MedlinePlus

Post-ischemic treatment with HDL does not decrease oxidation.Mice were submitted to LAD occlusion for 45min and hearts were reperfused for 24h. Mice were injected or not (control mice IR) with native HDL (nHDL), reHDLB (apoAI + POPC + S1P) one minute before reperfusion. A. Quantification of Di-BrY content of frozen sections of infarcted hearts after 24h of reperfusion. B. Representative images of Di-BrY stained middle heart sections. C. Correlation between neutrophil content and Di-BrY staining after 24h of reperfusion in the same hearts.
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pone.0119664.g006: Post-ischemic treatment with HDL does not decrease oxidation.Mice were submitted to LAD occlusion for 45min and hearts were reperfused for 24h. Mice were injected or not (control mice IR) with native HDL (nHDL), reHDLB (apoAI + POPC + S1P) one minute before reperfusion. A. Quantification of Di-BrY content of frozen sections of infarcted hearts after 24h of reperfusion. B. Representative images of Di-BrY stained middle heart sections. C. Correlation between neutrophil content and Di-BrY staining after 24h of reperfusion in the same hearts.

Mentions: HDL are known to modulate the inflammatory response. We investigated this possibility with the in vivo model. These experiments were limited to the most protective treatments: native HDL and rHDLB. We could not find evidence of a reduction in circulating levels of chemokines CCL2 or CXCL1 by treatment with native HDL or rHDLB, compared to controls (Table 1). Therefore, we extended our investigations to the inflammatory process within the cardiac tissue. As shown in Fig. 5, after 24h reperfusion neither native HDL nor rHDLB modulated neutrophil (Fig. 5A-5D) or macrophage (Fig. 5E, 5F) infiltration of the myocardial tissue compared to controls. Similarly, HDL treatment did not decrease myeloperoxidase-induced protein oxidation as measured using Di-BrY as a marker (Fig. 6A-6C). Moreover, histological analysis demonstrated that HDL treatment did not modulate myocardial lipid peroxidation (measured by 4-hydroxy-2-nonenal (4-HNE) staining) and superoxide (measured by dihydroethidium (DHE) staining) 24h after reperfusion (see S6 Fig.). Thus, one single injection of HDL at reperfusion did not significantly reduce the inflammatory response induced by ischemia.


Improving reconstituted HDL composition for efficient post-ischemic reduction of ischemia reperfusion injury.

Brulhart-Meynet MC, Braunersreuther V, Brinck J, Montecucco F, Prost JC, Thomas A, Galan K, Pelli G, Pedretti S, Vuilleumier N, Mach F, Lecour S, James RW, Frias MA - PLoS ONE (2015)

Post-ischemic treatment with HDL does not decrease oxidation.Mice were submitted to LAD occlusion for 45min and hearts were reperfused for 24h. Mice were injected or not (control mice IR) with native HDL (nHDL), reHDLB (apoAI + POPC + S1P) one minute before reperfusion. A. Quantification of Di-BrY content of frozen sections of infarcted hearts after 24h of reperfusion. B. Representative images of Di-BrY stained middle heart sections. C. Correlation between neutrophil content and Di-BrY staining after 24h of reperfusion in the same hearts.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362758&req=5

pone.0119664.g006: Post-ischemic treatment with HDL does not decrease oxidation.Mice were submitted to LAD occlusion for 45min and hearts were reperfused for 24h. Mice were injected or not (control mice IR) with native HDL (nHDL), reHDLB (apoAI + POPC + S1P) one minute before reperfusion. A. Quantification of Di-BrY content of frozen sections of infarcted hearts after 24h of reperfusion. B. Representative images of Di-BrY stained middle heart sections. C. Correlation between neutrophil content and Di-BrY staining after 24h of reperfusion in the same hearts.
Mentions: HDL are known to modulate the inflammatory response. We investigated this possibility with the in vivo model. These experiments were limited to the most protective treatments: native HDL and rHDLB. We could not find evidence of a reduction in circulating levels of chemokines CCL2 or CXCL1 by treatment with native HDL or rHDLB, compared to controls (Table 1). Therefore, we extended our investigations to the inflammatory process within the cardiac tissue. As shown in Fig. 5, after 24h reperfusion neither native HDL nor rHDLB modulated neutrophil (Fig. 5A-5D) or macrophage (Fig. 5E, 5F) infiltration of the myocardial tissue compared to controls. Similarly, HDL treatment did not decrease myeloperoxidase-induced protein oxidation as measured using Di-BrY as a marker (Fig. 6A-6C). Moreover, histological analysis demonstrated that HDL treatment did not modulate myocardial lipid peroxidation (measured by 4-hydroxy-2-nonenal (4-HNE) staining) and superoxide (measured by dihydroethidium (DHE) staining) 24h after reperfusion (see S6 Fig.). Thus, one single injection of HDL at reperfusion did not significantly reduce the inflammatory response induced by ischemia.

Bottom Line: Acute post-ischemic treatment with native HDL significantly reduced infarct size and cell death in the ex vivo, isolated heart (Langendorff) model and the in vivo model (-48%, p<0.01).This impact was comparable with the effects observed with native HDL.HDL afford protection against IRI in a clinically relevant model (post-ischemia). rHDL is significantly protective if supplemented with S1P.

View Article: PubMed Central - PubMed

Affiliation: Service of Endocrinology, Diabetology, Hypertension and Nutrition, Department of Internal Medicine, Faculty of Medicine, Geneva, Switzerland.

ABSTRACT

Background: New evidence shows that high density lipoproteins (HDL) have protective effects beyond their role in reverse cholesterol transport. Reconstituted HDL (rHDL) offer an attractive means of clinically exploiting these novel effects including cardioprotection against ischemia reperfusion injury (IRI). However, basic rHDL composition is limited to apolipoprotein AI (apoAI) and phospholipids; addition of bioactive compound may enhance its beneficial effects.

Objective: The aim of this study was to investigate the role of rHDL in post-ischemic model, and to analyze the potential impact of sphingosine-1-phosphate (S1P) in rHDL formulations.

Methods and results: The impact of HDL on IRI was investigated using complementary in vivo, ex vivo and in vitro IRI models. Acute post-ischemic treatment with native HDL significantly reduced infarct size and cell death in the ex vivo, isolated heart (Langendorff) model and the in vivo model (-48%, p<0.01). Treatment with rHDL of basic formulation (apoAI + phospholipids) had a non-significant impact on cell death in vitro and on the infarct size ex vivo and in vivo. In contrast, rHDL containing S1P had a highly significant, protective influence ex vivo, and in vivo (-50%, p<0.01). This impact was comparable with the effects observed with native HDL. Pro-survival signaling proteins, Akt, STAT3 and ERK1/2 were similarly activated by HDL and rHDL containing S1P both in vitro (isolated cardiomyocytes) and in vivo.

Conclusion: HDL afford protection against IRI in a clinically relevant model (post-ischemia). rHDL is significantly protective if supplemented with S1P. The protective impact of HDL appears to target directly the cardiomyocyte.

Show MeSH
Related in: MedlinePlus