Abstract:
AIMS:Protein Kinase R (PKR) plays a key role in inflammation and insulin resistance. Cytokines, high fat diet, infection and various stress signals can activate PKR. However, the functional significance of PKR in diabetic cardiomyopathy (DCM) is not explored so far. Thus the aim of the present study was to investigate the role of PKR in DCM in vivo in a rat model of DCM and underlying molecular mechanism. METHODS AND RESULTS:DCM was induced in Wistar rats by recipe of high fat diet and single injection of streptozotocin. Vital parameters were measured by non-invasive BP apparatus. Morphology, fibrosis and protein expression in heart was done by haematoxylin & eosin staining, masson's trichome/sirius red staining and western blotting respectively. For molecular mechanism studies, PKR gene silencing was done in cultured H9C2 cardiomyocytes and effect was observed in the presence of high glucose and high fat. Significant upregulation of PKR along with increase in cardiac biomarkers, decreased systolic and diastolic cardiac functions, oxidative stress, inflammatory markers, markers of fibrosis, enhanced cell death and AGEs' was observed in DCM disease model. Moreover, selective inhibition of PKR alleviated cardiac dysfunction, fibrosis, oxidative stress, inflammation and cell death. Additionally knockdown of PKR attenuated glucolipotoxicty-induced markers of inflammation, oxidative stress and apoptosis in cultured H9C2 cardiomyocytes. CONCLUSION:Our present study reports for the first time that inhibition of PKR may have great therapeutic potential in the treatment of DCM by attenuating inflammation, oxidative stress, apoptosis and fibrosis.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Mangali S,Bhat A,Jadhav K,Kalra J,Sriram D,Vamsi Krishna Venuganti V,Dhar Adoi
10.1016/j.bcp.2020.113948subject
Has Abstractpub_date
2020-07-01 00:00:00pages
113948eissn
0006-2952issn
1873-2968pii
S0006-2952(20)30176-3journal_volume
177pub_type
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