Samah S Abbas1, Hesham M Mahmoud2, Mona F Schaalan3, Hanan S El-Abhar4. 1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Misr International University, Cairo, Egypt. Electronic address: samah.saeed@miuegypt.edu.eg. 2. Department of Medical Pharmacology, Faculty of Medicine, Cairo University, Cairo, Egypt. 3. Department of Biochemistry, Faculty of Pharmacy, Misr International University, Cairo, Egypt. 4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Abstract
BACKGROUND: The current study is focusing on the role of brain natriuretic peptide (BNP), a substrate of dipeptidyl peptidase-4 (DPP-4) enzyme, and its signaling survival pathway in the cardioprotective mechanism of sitagliptin, a DPP-4 inhibitor. METHODS: Male Wistar rats were randomized into 7 groups, sham, I/R, KT-5823 (selective protein kinase (PK) G inhibitor), 5-HD (selective mito-KATP channel blocker), sitagliptin (300mg/kg, po), sitagliptin+KT-5823, and sitagliptin+5-HD. Sitagliptin was administered for 3 days prior to induction of coronary I/R, while either KT-5823 or 5-HD was administered intravenously 5min before coronary ligation. RESULTS: Pretreatment with sitagliptin provided significant protection against I/R injury as manifested by decreasing, percentage of infarct size, suppressing the elevated ST segment, reducing the increased cardiac enzymes, as well as DPP-4 activity and elevating both heart rate (HR) and left ventricular developed pressure (LVDP). However, the addition of either blocker to sitagliptin regimen reversed partly its cardioprotective effects. Although I/R increased BNP content, it unexpectedly decreased that of cGMP; nevertheless, sitagliptin elevated both parameters, an effect that was not affected by the use of the two blockers. On the molecular level, sitagliptin decreased caspase-3 activity and downregulated the mRNA levels of BNP, Bax, and Cyp D, while upregulated that of Bcl2. The use of either KT-5823 or 5-HD with sitagliptin hindered its effect on the molecular markers tested. CONCLUSIONS: The results of the present study suggest that the cardioprotective effect of sitagliptin is mediated partly, but not solely, through the BNP/cGMP/PKG survival signaling pathway.
BACKGROUND: The current study is focusing on the role of brain natriuretic peptide (BNP), a substrate of dipeptidyl peptidase-4 (DPP-4) enzyme, and its signaling survival pathway in the cardioprotective mechanism of sitagliptin, a DPP-4 inhibitor. METHODS: Male Wistar rats were randomized into 7 groups, sham, I/R, KT-5823 (selective protein kinase (PK) G inhibitor), 5-HD (selective mito-KATP channel blocker), sitagliptin (300mg/kg, po), sitagliptin+KT-5823, and sitagliptin+5-HD. Sitagliptin was administered for 3 days prior to induction of coronary I/R, while either KT-5823 or 5-HD was administered intravenously 5min before coronary ligation. RESULTS: Pretreatment with sitagliptin provided significant protection against I/R injury as manifested by decreasing, percentage of infarct size, suppressing the elevated ST segment, reducing the increased cardiac enzymes, as well as DPP-4 activity and elevating both heart rate (HR) and left ventricular developed pressure (LVDP). However, the addition of either blocker to sitagliptin regimen reversed partly its cardioprotective effects. Although I/R increased BNP content, it unexpectedly decreased that of cGMP; nevertheless, sitagliptin elevated both parameters, an effect that was not affected by the use of the two blockers. On the molecular level, sitagliptin decreased caspase-3 activity and downregulated the mRNA levels of BNP, Bax, and Cyp D, while upregulated that of Bcl2. The use of either KT-5823 or 5-HD with sitagliptin hindered its effect on the molecular markers tested. CONCLUSIONS: The results of the present study suggest that the cardioprotective effect of sitagliptin is mediated partly, but not solely, through the BNP/cGMP/PKG survival signaling pathway.
Authors: Esraa M Zakaria; Walaa M Tawfeek; Mohamed H Hassanin; Mohammed Y Hassaballah Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2022-08-10 Impact factor: 3.195