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Involvement of Brain Natriuretic Peptide Signaling Pathway in the Cardioprotective Action of Sitagliptin

Involvement of Brain Natriuretic Peptide Signaling Pathway in the Cardioprotective Action of Sitagliptin

Samah S Abbas, Hesham M Mahmoud, Mona F Schaalan, Hanan S El-Abhar

Pharmacol Rep. 2018 Aug;70(4):720-729.

PMID: 29935398

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP126643376-A	KT 5823		126643-37-6	Price

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