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Endocardial Endothelial Dysfunction Progressively Disrupts Initially Anti then Pro-Thrombotic Pathways in Heart Failure Mice.

Schoner A, Tyrrell C, Wu M, Gelow JM, Hayes AA, Lindner JR, Thornburg KL, Hasan W - PLoS ONE (2015)

Bottom Line: An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied.Endocardial thrombi incidence was confirmed with immunohistochemistry and histology.Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF.

View Article: PubMed Central - PubMed

Affiliation: Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States of America.

ABSTRACT

Objective: An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied. We sought to determine whether disruption of the endothelial anti-coagulant activated protein C (APC) pathway in CREBA133 HF mice promotes endocardial thrombosis in the acute decompensated phase of the disease, and whether alterations in von Willebrand factor (vWF) secretion from HF endocardium reduces thrombus formation as HF stabilizes.

Approach and results: Echocardiography was used to follow HF development and to detect endocardial thrombi in CREBA133 mice. Endocardial thrombi incidence was confirmed with immunohistochemistry and histology. In early and acute decompensated phases of HF, CREBA133 mice had the highest incidence of endocardial thrombi and these mice also had a shorter tail-bleeding index consistent with a pro-thrombotic milieu. Both APC generation, and expression of receptors that promote APC function (thrombomodulin, endothelial protein C receptor, protein S), were suppressed in the endocardium of acute decompensated HF mice. However, in stable compensated HF mice, an attenuation occurred for vWF protein content and secretion from endocardial endothelial cells, vWF-dependent platelet agglutination (by ristocetin), and thrombin generation on the endocardial surface.

Conclusions: CREBA133 mice develop HF and endocardial endothelial dysfunction. Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF. However, in stable compensated HF mice, disruptions in endothelial vWF expression and extrusion may actually reduce the incidence of endocardial thrombosis.

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Thrombin (FIIa; A) and APC (B) generation, and TM (C, D), EPCR (E, F), and Protein S (G, H) expression, on the endocardial surface of wildtype, all HF (HF), early HF, acute HF, and chronic HF mice.Thrombin generation is increased in acute HF compared to wildtype mice (A). APC generation is decreased in all HF mice compared to wildtype mice (B). TM (C) and EPCR (E) mRNA expression is attenuated in all HF mice groups compared to wildtype mice. Protein S (G) transcripts are also decreased in early and chronic HF mice. Protein expression of TM (D) and Protein S (H) is decreased in chronic HF compared to wildtype mice. EPCR (F) protein expression is attenuated in early and acute HF mice relative to wildtype and chronic HF mice. *p<0.05, **p<0.01, ***p<0.005.
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pone.0142940.g004: Thrombin (FIIa; A) and APC (B) generation, and TM (C, D), EPCR (E, F), and Protein S (G, H) expression, on the endocardial surface of wildtype, all HF (HF), early HF, acute HF, and chronic HF mice.Thrombin generation is increased in acute HF compared to wildtype mice (A). APC generation is decreased in all HF mice compared to wildtype mice (B). TM (C) and EPCR (E) mRNA expression is attenuated in all HF mice groups compared to wildtype mice. Protein S (G) transcripts are also decreased in early and chronic HF mice. Protein expression of TM (D) and Protein S (H) is decreased in chronic HF compared to wildtype mice. EPCR (F) protein expression is attenuated in early and acute HF mice relative to wildtype and chronic HF mice. *p<0.05, **p<0.01, ***p<0.005.

Mentions: Activity assays for thrombin generation on the endocardial surface showed an increase in thrombin (FIIa) generation in acute HF compared to both wildtype (65.5%) and early HF (40%) mice (Fig 4A). In contrast, chronic HF mice had lower FIIa generation than all other groups (85–91% decreases). APC generation on the endocardial surface was attenuated in all HF groups (by 71.4% in early, 42.5% in acute, 43.3% in chronic HF) compared to wildtype LVs (Fig 4B).


Endocardial Endothelial Dysfunction Progressively Disrupts Initially Anti then Pro-Thrombotic Pathways in Heart Failure Mice.

Schoner A, Tyrrell C, Wu M, Gelow JM, Hayes AA, Lindner JR, Thornburg KL, Hasan W - PLoS ONE (2015)

Thrombin (FIIa; A) and APC (B) generation, and TM (C, D), EPCR (E, F), and Protein S (G, H) expression, on the endocardial surface of wildtype, all HF (HF), early HF, acute HF, and chronic HF mice.Thrombin generation is increased in acute HF compared to wildtype mice (A). APC generation is decreased in all HF mice compared to wildtype mice (B). TM (C) and EPCR (E) mRNA expression is attenuated in all HF mice groups compared to wildtype mice. Protein S (G) transcripts are also decreased in early and chronic HF mice. Protein expression of TM (D) and Protein S (H) is decreased in chronic HF compared to wildtype mice. EPCR (F) protein expression is attenuated in early and acute HF mice relative to wildtype and chronic HF mice. *p<0.05, **p<0.01, ***p<0.005.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4643996&req=5

pone.0142940.g004: Thrombin (FIIa; A) and APC (B) generation, and TM (C, D), EPCR (E, F), and Protein S (G, H) expression, on the endocardial surface of wildtype, all HF (HF), early HF, acute HF, and chronic HF mice.Thrombin generation is increased in acute HF compared to wildtype mice (A). APC generation is decreased in all HF mice compared to wildtype mice (B). TM (C) and EPCR (E) mRNA expression is attenuated in all HF mice groups compared to wildtype mice. Protein S (G) transcripts are also decreased in early and chronic HF mice. Protein expression of TM (D) and Protein S (H) is decreased in chronic HF compared to wildtype mice. EPCR (F) protein expression is attenuated in early and acute HF mice relative to wildtype and chronic HF mice. *p<0.05, **p<0.01, ***p<0.005.
Mentions: Activity assays for thrombin generation on the endocardial surface showed an increase in thrombin (FIIa) generation in acute HF compared to both wildtype (65.5%) and early HF (40%) mice (Fig 4A). In contrast, chronic HF mice had lower FIIa generation than all other groups (85–91% decreases). APC generation on the endocardial surface was attenuated in all HF groups (by 71.4% in early, 42.5% in acute, 43.3% in chronic HF) compared to wildtype LVs (Fig 4B).

Bottom Line: An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied.Endocardial thrombi incidence was confirmed with immunohistochemistry and histology.Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF.

View Article: PubMed Central - PubMed

Affiliation: Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States of America.

ABSTRACT

Objective: An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied. We sought to determine whether disruption of the endothelial anti-coagulant activated protein C (APC) pathway in CREBA133 HF mice promotes endocardial thrombosis in the acute decompensated phase of the disease, and whether alterations in von Willebrand factor (vWF) secretion from HF endocardium reduces thrombus formation as HF stabilizes.

Approach and results: Echocardiography was used to follow HF development and to detect endocardial thrombi in CREBA133 mice. Endocardial thrombi incidence was confirmed with immunohistochemistry and histology. In early and acute decompensated phases of HF, CREBA133 mice had the highest incidence of endocardial thrombi and these mice also had a shorter tail-bleeding index consistent with a pro-thrombotic milieu. Both APC generation, and expression of receptors that promote APC function (thrombomodulin, endothelial protein C receptor, protein S), were suppressed in the endocardium of acute decompensated HF mice. However, in stable compensated HF mice, an attenuation occurred for vWF protein content and secretion from endocardial endothelial cells, vWF-dependent platelet agglutination (by ristocetin), and thrombin generation on the endocardial surface.

Conclusions: CREBA133 mice develop HF and endocardial endothelial dysfunction. Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF. However, in stable compensated HF mice, disruptions in endothelial vWF expression and extrusion may actually reduce the incidence of endocardial thrombosis.

Show MeSH
Related in: MedlinePlus