Tags

Type your tag names separated by a space and hit enter

Argatroban Attenuates Diabetic Cardiomyopathy in Rats by Reducing Fibrosis, Inflammation, Apoptosis, and Protease-Activated Receptor Expression.
Cardiovasc Drugs Ther. 2017 Jun; 31(3):255-267.CD

Abstract

PURPOSE

Chronic diabetes is associated with cardiovascular dysfunctions. Diabetic cardiomyopathy (DCM) is one of the serious cardiovascular complications associated with diabetes. Despite significant efforts in understanding the pathophysiology of DCM, management of DCM is not adequate due to its complex pathophysiology. Recently, involvement of protease-activated receptors (PARs) has been postulated in cardiovascular diseases. These receptors are activated by thrombin, trypsin, or other serine proteases. Expression of PAR has been shown to be increased in cardiac diseases such as myocardial infarction, viral myocarditis, and pulmonary arterial hypertension. However, the role of PAR in DCM has not been elucidated yet. Therefore, in the present study, we have investigated the role of PAR in the condition of DCM using a pharmacological approach. We used argatroban, a direct thrombin inhibitor for targeting PAR.

METHODS

Type-2 diabetes mellitus (T2DM) was induced by high-fat feeding along with low dose streptozotocin (STZ 35 mg/kg, i.p. single dose) in male Sprague-Dawley rats. After 16 weeks of diabetes induction, animals were treated with argatroban at 0.3 and 1 mg/kg dose daily for 4 weeks. After 20 weeks, ventricular functions were measured using ventricular catheterization. Cardiac histology, TUNEL staining, and immunoblotting were performed to evaluate cardiac fibrosis, DNA fragmentation, and expression level of different proteins, respectively.

RESULTS

T2DM was associated with cardiac structural and functional disturbances as evidenced from impaired cardiac functional parameters and increased fibrosis. There was a significant increase in PAR expression after 20 weeks of diabetes induction. Four weeks argatroban treatment ameliorated metabolic alterations (reduced plasma glucose and cholesterol), ventricular dysfunctions (improved systolic and diastolic functions), cardiac fibrosis (reduced percentage area of collagen in picro-sirius red staining), and apoptosis (reduced TUNEL positive nuclei). Reduced expression of PAR1 and PAR4 in the argatroban-treated group indicates a response towards inhibition of thrombin. In addition, AKT (Ser-473), GSK-3β (Ser-9), p-65 NFĸB phosphorylation, TGF-β, COX-2, and caspase-3 expression were reduced significantly along with an increase in SERCA expression in argatroban-treated diabetic rats which indicated the anti-fibrotic, anti-inflammatory, and anti-apoptotic potential of argatroban in DCM.

CONCLUSION

This study suggests the ameliorative effects of argatroban in diabetic cardiomyopathy by improving ventricular functions and reducing fibrosis, inflammation, apoptosis, and PAR expression.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, SAS, Nagar (Mohali), Punjab, 160062, India.Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, SAS, Nagar (Mohali), Punjab, 160062, India. sssharma@niper.ac.in.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28695302

Citation

Bulani, Yogesh, and Shyam Sunder Sharma. "Argatroban Attenuates Diabetic Cardiomyopathy in Rats By Reducing Fibrosis, Inflammation, Apoptosis, and Protease-Activated Receptor Expression." Cardiovascular Drugs and Therapy, vol. 31, no. 3, 2017, pp. 255-267.
Bulani Y, Sharma SS. Argatroban Attenuates Diabetic Cardiomyopathy in Rats by Reducing Fibrosis, Inflammation, Apoptosis, and Protease-Activated Receptor Expression. Cardiovasc Drugs Ther. 2017;31(3):255-267.
Bulani, Y., & Sharma, S. S. (2017). Argatroban Attenuates Diabetic Cardiomyopathy in Rats by Reducing Fibrosis, Inflammation, Apoptosis, and Protease-Activated Receptor Expression. Cardiovascular Drugs and Therapy, 31(3), 255-267. https://doi.org/10.1007/s10557-017-6732-3
Bulani Y, Sharma SS. Argatroban Attenuates Diabetic Cardiomyopathy in Rats By Reducing Fibrosis, Inflammation, Apoptosis, and Protease-Activated Receptor Expression. Cardiovasc Drugs Ther. 2017;31(3):255-267. PubMed PMID: 28695302.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Argatroban Attenuates Diabetic Cardiomyopathy in Rats by Reducing Fibrosis, Inflammation, Apoptosis, and Protease-Activated Receptor Expression. AU - Bulani,Yogesh, AU - Sharma,Shyam Sunder, PY - 2017/7/12/pubmed PY - 2018/7/13/medline PY - 2017/7/12/entrez KW - Argatroban KW - Diabetic cardiomyopathy KW - Fibrosis KW - Protease activated receptors KW - Ventricular functions SP - 255 EP - 267 JF - Cardiovascular drugs and therapy JO - Cardiovasc Drugs Ther VL - 31 IS - 3 N2 - PURPOSE: Chronic diabetes is associated with cardiovascular dysfunctions. Diabetic cardiomyopathy (DCM) is one of the serious cardiovascular complications associated with diabetes. Despite significant efforts in understanding the pathophysiology of DCM, management of DCM is not adequate due to its complex pathophysiology. Recently, involvement of protease-activated receptors (PARs) has been postulated in cardiovascular diseases. These receptors are activated by thrombin, trypsin, or other serine proteases. Expression of PAR has been shown to be increased in cardiac diseases such as myocardial infarction, viral myocarditis, and pulmonary arterial hypertension. However, the role of PAR in DCM has not been elucidated yet. Therefore, in the present study, we have investigated the role of PAR in the condition of DCM using a pharmacological approach. We used argatroban, a direct thrombin inhibitor for targeting PAR. METHODS: Type-2 diabetes mellitus (T2DM) was induced by high-fat feeding along with low dose streptozotocin (STZ 35 mg/kg, i.p. single dose) in male Sprague-Dawley rats. After 16 weeks of diabetes induction, animals were treated with argatroban at 0.3 and 1 mg/kg dose daily for 4 weeks. After 20 weeks, ventricular functions were measured using ventricular catheterization. Cardiac histology, TUNEL staining, and immunoblotting were performed to evaluate cardiac fibrosis, DNA fragmentation, and expression level of different proteins, respectively. RESULTS: T2DM was associated with cardiac structural and functional disturbances as evidenced from impaired cardiac functional parameters and increased fibrosis. There was a significant increase in PAR expression after 20 weeks of diabetes induction. Four weeks argatroban treatment ameliorated metabolic alterations (reduced plasma glucose and cholesterol), ventricular dysfunctions (improved systolic and diastolic functions), cardiac fibrosis (reduced percentage area of collagen in picro-sirius red staining), and apoptosis (reduced TUNEL positive nuclei). Reduced expression of PAR1 and PAR4 in the argatroban-treated group indicates a response towards inhibition of thrombin. In addition, AKT (Ser-473), GSK-3β (Ser-9), p-65 NFĸB phosphorylation, TGF-β, COX-2, and caspase-3 expression were reduced significantly along with an increase in SERCA expression in argatroban-treated diabetic rats which indicated the anti-fibrotic, anti-inflammatory, and anti-apoptotic potential of argatroban in DCM. CONCLUSION: This study suggests the ameliorative effects of argatroban in diabetic cardiomyopathy by improving ventricular functions and reducing fibrosis, inflammation, apoptosis, and PAR expression. SN - 1573-7241 UR - https://www.unboundmedicine.com/medline/citation/28695302/Argatroban_Attenuates_Diabetic_Cardiomyopathy_in_Rats_by_Reducing_Fibrosis_Inflammation_Apoptosis_and_Protease_Activated_Receptor_Expression_ L2 - https://doi.org/10.1007/s10557-017-6732-3 DB - PRIME DP - Unbound Medicine ER -