Ticagrelor Improves Remodeling, Reduces Apoptosis, Inflammation and Fibrosis and Increases the Number of Progenitor Stem Cells After Myocardial Infarction in a Rat Model of Ischemia Reperfusion.
Animals
Apoptosis
/ drug effects
Aspirin
/ pharmacology
Atrial Natriuretic Factor
/ genetics
Disease Models, Animal
Drug Therapy, Combination
Endoglin
/ genetics
Fibrosis
Gene Expression Regulation
/ drug effects
Myocardial Infarction
/ drug therapy
Myocardial Reperfusion Injury
/ metabolism
Platelet Aggregation Inhibitors
/ pharmacology
Prasugrel Hydrochloride
/ pharmacology
Proto-Oncogene Proteins c-kit
/ genetics
Rats
Rats, Sprague-Dawley
Stem Cells
/ cytology
Ticagrelor
/ pharmacology
Ventricular Function, Left
/ drug effects
Ventricular Remodeling
/ drug effects
Apoptosis; Aspirin; Fibrosis; Inflammation; Ischemia-reperfusion; Prasugrel; Remodeling; Stem cells; Ticagrelor
Journal
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
ISSN: 1421-9778
Titre abrégé: Cell Physiol Biochem
Pays: Germany
ID NLM: 9113221
Informations de publication
Date de publication:
2019
2019
Historique:
accepted:
05
12
2019
entrez:
11
12
2019
pubmed:
11
12
2019
medline:
24
12
2019
Statut:
ppublish
Résumé
We assessed the effects of ticagrelor, aspirin and prasugrel, started 7days after myocardial ischemia-reperfusion injury on remodeling, inflammation and fibrosis in the rat. We examined whether ticagrelor can affect the number of progenitor cells in the border zone. Ticagrelor, started 24h after myocardial ischemia-reperfusion injury, attenuates the decrease in heart function and adverse remodeling, an effect which is blocked by aspirin. Rats underwent 40min ischemia followed by reperfusion. Oral dosing with vehicle, ticagrelor (300mg/kg/d), aspirin (20mg/kg/d), their combination or prasugrel (15mg/kg/d) started 7days after infarction. Echocardiography was used to assess systolic function. Heart tissue were analyzed by rt-PCR, immunoblotting, ELISA and immunohistochemistry 2weeks after infarction. Both ticagrelor and aspirin attenuated the decrease in systolic function and remodeling, an effect that was blocked by their combination. Ticagrelor and aspirin attenuated the increase in ANP, BNP, collagen-I and collagen-III. Again, the effect was blocked by their combination. Ticagrelor increased c-Kit, Sca-1, Ki-67, CD34, attenuated the decrease in CD105 mRNA levels, and attenuated the increase in CD31, whereas aspirin increased Ki-67, suppressed the increase in CD31 and attenuated the decrease in CD105 mRNA levels. Prasugrel did not display any effects. Ticagrelor attenuated adverse remodeling and deterioration of left ventricular systolic function despite starting treatment after the myocardial ischemia-reperfusion injury is completed. Aspirin had similar effects; however, when combined with ticagrelor, the protective effects were significantly attenuated. Ticagrelor increased the levels of several markers of stem cells and regeneration, suggesting cardiac healing by recruiting regenerative cells into the infarct.
Sections du résumé
BACKGROUND/AIMS
OBJECTIVE
We assessed the effects of ticagrelor, aspirin and prasugrel, started 7days after myocardial ischemia-reperfusion injury on remodeling, inflammation and fibrosis in the rat. We examined whether ticagrelor can affect the number of progenitor cells in the border zone. Ticagrelor, started 24h after myocardial ischemia-reperfusion injury, attenuates the decrease in heart function and adverse remodeling, an effect which is blocked by aspirin.
METHODS
METHODS
Rats underwent 40min ischemia followed by reperfusion. Oral dosing with vehicle, ticagrelor (300mg/kg/d), aspirin (20mg/kg/d), their combination or prasugrel (15mg/kg/d) started 7days after infarction. Echocardiography was used to assess systolic function. Heart tissue were analyzed by rt-PCR, immunoblotting, ELISA and immunohistochemistry 2weeks after infarction.
RESULTS
RESULTS
Both ticagrelor and aspirin attenuated the decrease in systolic function and remodeling, an effect that was blocked by their combination. Ticagrelor and aspirin attenuated the increase in ANP, BNP, collagen-I and collagen-III. Again, the effect was blocked by their combination. Ticagrelor increased c-Kit, Sca-1, Ki-67, CD34, attenuated the decrease in CD105 mRNA levels, and attenuated the increase in CD31, whereas aspirin increased Ki-67, suppressed the increase in CD31 and attenuated the decrease in CD105 mRNA levels. Prasugrel did not display any effects.
CONCLUSION
CONCLUSIONS
Ticagrelor attenuated adverse remodeling and deterioration of left ventricular systolic function despite starting treatment after the myocardial ischemia-reperfusion injury is completed. Aspirin had similar effects; however, when combined with ticagrelor, the protective effects were significantly attenuated. Ticagrelor increased the levels of several markers of stem cells and regeneration, suggesting cardiac healing by recruiting regenerative cells into the infarct.
Substances chimiques
Endoglin
0
Platelet Aggregation Inhibitors
0
Atrial Natriuretic Factor
85637-73-6
Proto-Oncogene Proteins c-kit
EC 2.7.10.1
Prasugrel Hydrochloride
G89JQ59I13
Ticagrelor
GLH0314RVC
Aspirin
R16CO5Y76E
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
961-981Subventions
Organisme : AstraZeneca
Pays : Sweden
Informations de copyright
© Copyright by the Author(s). Published by Cell Physiol Biochem Press.
Déclaration de conflit d'intérêts
Dr. Nylander is an employee of AstraZeneca. Dr. Ye receives research grants from AstraZeneca and Boehringer Ingelheim. Dr. Yochai Birnbaum receives research grants from AstraZeneca.