Peripheral leucocytes and tissue gene expression of granzyme B/perforin system and serpinB9: Impact on inflammation and insulin resistance in coronary atherosclerosis

• Published in: Diabetes research and clinical practice 2017-09, Vol.131, p.132-141
• Main Authors: Sanad, Eman F., Hamdy, Nadia M., El-Etriby, Adel K., Sebak, Samer A., El-Mesallamy, Hala O.
• Format: Article
• Language: English
• Subjects: Aged; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Coronary Artery Disease - genetics; Coronary Artery Disease - metabolism; Female; Granzyme B; Granzymes - metabolism; Humans; Inflammation; Inflammation - metabolism; Insulin resistance; Insulin Resistance - physiology; Leukocytes - metabolism; Male; Middle Aged; Perforin; Perforin - metabolism; Proteinase inhibitor 9; Recombinant Fusion Proteins - metabolism; Retrospective Studies; Serpins - metabolism
• ISSN: 0168-8227; 1872-8227
• DOI: 10.1016/j.diabres.2017.07.013

•Atherosclerotic vessels contain more GZB and low PI-9 that is exacerbated by type 2 DM.•High GZB and low PI-9 are directly and indirectly contributed to inflammation and insulin resistance.•Circulating PI-9 mRNA levels might be a marker of CAD severity. The imbalance between proapoptotic granzyme B (GZB)/perforin (PRF) system and proteinase inhibitor-9 (PI-9; serpinB9); the only known inhibitor of human GZB, has been demonstrated in atherosclerosis. However, their role in atherosclerosis with the impact of type 2 diabetes mellitus (DM) as well as their contribution to hallmarks of atherosclerosis is not clear. ELISA for serum insulin, high sensitivity C-reactive protein (hsCRP) and GZB levels in atherosclerotic coronary artery diseases (CAD) patients were estimated in comparison to apparently healthy controls, while GZB, PRF and PI-9 mRNA expression levels were quantified by Taqman RT-PCR in both peripheral leucocytes and atherosclerotic tissues. Atherosclerotic patients showed significantly higher insulin, hsCRP and GZB levels than controls. There was a significant increase in GZB mRNA expression and significant reduction in PI-9 mRNA in both patient peripheral leucocytes and atherosclerotic lesions, while PRF mRNA increased significantly only in atherosclerotic tissues. PI-9 mRNA levels were significantly lower in patients with diabetes than patients without diabetes. In contrast to positive modulating effect of GZB, regression analysis revealed negative modulating effect of PI-9 on inflammation and insulin resistance. Circulating PI-9 mRNA was inversely contributed to CAD severity. GZB and PI-9 could be effective modulators for inflammation and insulin resistance in atherosclerosis.