Pretreatment with PCSK9 inhibitor protects the brain against cardiac ischemia/reperfusion injury through a reduction of neuronal inflammation and amyloid beta aggregation
© 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. Background Cardiac ischemic/reperfusion (I/R) injury leads to brain damage. A new antihyperlipidemic drug is aimed at inhibitingPCSK9 (proprotein convertase subtilisin/kexin type 9), a molecule first identifi...
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th-cmuir.6653943832-637212019-03-18T02:24:46Z Pretreatment with PCSK9 inhibitor protects the brain against cardiac ischemia/reperfusion injury through a reduction of neuronal inflammation and amyloid beta aggregation Nattayaporn Apaijai Dalila Monica Moisescu Siripong Palee Christian Mervyn McSweeney Napatsorn Saiyasit Chayodom Maneechote Chiraphat Boonnag Nipon Chattipakorn Siriporn C. Chattipakorn Medicine © 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. Background Cardiac ischemic/reperfusion (I/R) injury leads to brain damage. A new antihyperlipidemic drug is aimed at inhibitingPCSK9 (proprotein convertase subtilisin/kexin type 9), a molecule first identified in a neuronal apoptosis paradigm. Thus, thePCSK9 inhibitor (PCSK9i) may play a role in neuronal recovery following cardiac I/R insults. We hypothesize thatPCSK9i attenuates brain damage caused by cardiac I/R via diminishing microglial/astrocytic hyperactivation, β-amyloid aggregation, and loss of dendritic spine. Methods and Results Adult male rats were divided into 7 groups: (1) control (n=4); (2)PCSK9i without cardiac I/R (n=4); (3) sham (n=4); and cardiac I/R (n=40). Cardiac I/R rats were divided into 4 subgroups (n=10/subgroup): (1) vehicle; (2)PCSK9i (10μg/kg, IV) before ischemia; (3)PCSK9i during ischemia; and (4)PCSK9i at the onset of reperfusion. At the end of cardiac I/R protocol, brains were removed to determine microglial and astrocytic activities, β-amyloid aggravation, and dendritic spine density. The cardiac I/R led to the activation of the brain's innate immunity resulting in increasing Iba1 + microglia,GFAP + astrocytes, andCD11b + /CD45 +high cell numbers. However, CD11b + /CD45 +low cell numbers were decreased following cardiac I/R. In addition, cardiac I/R led to reduced dendritic spine density, and increased β-amyloid aggregation. Only the administration ofPCSK9i before ischemia effectively attenuated these deleterious effects on the brain following cardiac I/R.PCSK9i administration under the physiologic condition did not affect the aforementioned parameters. Conclusions Cardiac I/R injury activated microglial activity in the brain, leading to brain damage. Only the pretreatment withPCSK9i prevented dendritic spine loss via reduction of microglial activation and Aβ aggregation. 2019-03-18T02:24:46Z 2019-03-18T02:24:46Z 2019-01-01 Journal 20479980 2-s2.0-85059900929 10.1161/JAHA.118.010838 https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85059900929&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/63721 |
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Medicine Nattayaporn Apaijai Dalila Monica Moisescu Siripong Palee Christian Mervyn McSweeney Napatsorn Saiyasit Chayodom Maneechote Chiraphat Boonnag Nipon Chattipakorn Siriporn C. Chattipakorn Pretreatment with PCSK9 inhibitor protects the brain against cardiac ischemia/reperfusion injury through a reduction of neuronal inflammation and amyloid beta aggregation |
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© 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. Background Cardiac ischemic/reperfusion (I/R) injury leads to brain damage. A new antihyperlipidemic drug is aimed at inhibitingPCSK9 (proprotein convertase subtilisin/kexin type 9), a molecule first identified in a neuronal apoptosis paradigm. Thus, thePCSK9 inhibitor (PCSK9i) may play a role in neuronal recovery following cardiac I/R insults. We hypothesize thatPCSK9i attenuates brain damage caused by cardiac I/R via diminishing microglial/astrocytic hyperactivation, β-amyloid aggregation, and loss of dendritic spine. Methods and Results Adult male rats were divided into 7 groups: (1) control (n=4); (2)PCSK9i without cardiac I/R (n=4); (3) sham (n=4); and cardiac I/R (n=40). Cardiac I/R rats were divided into 4 subgroups (n=10/subgroup): (1) vehicle; (2)PCSK9i (10μg/kg, IV) before ischemia; (3)PCSK9i during ischemia; and (4)PCSK9i at the onset of reperfusion. At the end of cardiac I/R protocol, brains were removed to determine microglial and astrocytic activities, β-amyloid aggravation, and dendritic spine density. The cardiac I/R led to the activation of the brain's innate immunity resulting in increasing Iba1 + microglia,GFAP + astrocytes, andCD11b + /CD45 +high cell numbers. However, CD11b + /CD45 +low cell numbers were decreased following cardiac I/R. In addition, cardiac I/R led to reduced dendritic spine density, and increased β-amyloid aggregation. Only the administration ofPCSK9i before ischemia effectively attenuated these deleterious effects on the brain following cardiac I/R.PCSK9i administration under the physiologic condition did not affect the aforementioned parameters. Conclusions Cardiac I/R injury activated microglial activity in the brain, leading to brain damage. Only the pretreatment withPCSK9i prevented dendritic spine loss via reduction of microglial activation and Aβ aggregation. |
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Nattayaporn Apaijai Dalila Monica Moisescu Siripong Palee Christian Mervyn McSweeney Napatsorn Saiyasit Chayodom Maneechote Chiraphat Boonnag Nipon Chattipakorn Siriporn C. Chattipakorn |
author_facet |
Nattayaporn Apaijai Dalila Monica Moisescu Siripong Palee Christian Mervyn McSweeney Napatsorn Saiyasit Chayodom Maneechote Chiraphat Boonnag Nipon Chattipakorn Siriporn C. Chattipakorn |
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Nattayaporn Apaijai |
title |
Pretreatment with PCSK9 inhibitor protects the brain against cardiac ischemia/reperfusion injury through a reduction of neuronal inflammation and amyloid beta aggregation |
title_short |
Pretreatment with PCSK9 inhibitor protects the brain against cardiac ischemia/reperfusion injury through a reduction of neuronal inflammation and amyloid beta aggregation |
title_full |
Pretreatment with PCSK9 inhibitor protects the brain against cardiac ischemia/reperfusion injury through a reduction of neuronal inflammation and amyloid beta aggregation |
title_fullStr |
Pretreatment with PCSK9 inhibitor protects the brain against cardiac ischemia/reperfusion injury through a reduction of neuronal inflammation and amyloid beta aggregation |
title_full_unstemmed |
Pretreatment with PCSK9 inhibitor protects the brain against cardiac ischemia/reperfusion injury through a reduction of neuronal inflammation and amyloid beta aggregation |
title_sort |
pretreatment with pcsk9 inhibitor protects the brain against cardiac ischemia/reperfusion injury through a reduction of neuronal inflammation and amyloid beta aggregation |
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2019 |
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https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85059900929&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/63721 |
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