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The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Directly Enhances the Contractile Recovery of Mouse Hearts at a Concentration Equivalent to that Achieved with Standard Dosing in Humans

1
Keenan Research Center for Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada
2
Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(16), 5756; https://doi.org/10.3390/ijms21165756
Received: 14 June 2020 / Revised: 7 August 2020 / Accepted: 9 August 2020 / Published: 11 August 2020
(This article belongs to the Section Molecular Endocrinology and Metabolism)
Despite a similar mechanism of action underlying their glucose-lowering effects in type 2 diabetes, dipeptidyl peptidase-4 (DPP-4) inhibitors have diverse molecular structures, raising the prospect of agent-specific, glucose-independent actions. To explore the issue of possible DPP-4 inhibitor cardiac heterogeneity, we perfused different DPP-4 inhibitors to beating mouse hearts ex vivo, at concentrations equivalent to peak plasma levels achieved in humans with standard dosing. We studied male and female mice, young non-diabetic mice, and aged diabetic high fat diet-fed mice and observed that linagliptin enhanced recovery after ischemia-reperfusion, whereas sitagliptin, alogliptin, and saxagliptin did not. DPP-4 transcripts were not detected in adult mouse cardiomyocytes by RNA sequencing and the addition of linagliptin caused ≤0.2% of cardiomyocyte genes to be differentially expressed. In contrast, incubation of C166 endothelial cells with linagliptin induced cell signaling characterized by phosphorylation of Akt and endothelial nitric oxide synthase, whereas the nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine increased serine 16 phosphorylation of the calcium regulatory protein, phospholamban in cardiomyocytes. Furthermore, linagliptin increased cardiomyocyte cGMP when cells were co-cultured with C166 endothelial cells, but not when cardiomyocytes were cultured alone. Thus, at a concentration comparable to that achieved in patients, linagliptin has direct effects on mouse hearts. The effects of linagliptin on cardiomyocytes are likely to be either off-target or indirect, mediated through NO generation by the adjacent cardiac endothelium. View Full-Text
Keywords: DPP-4 inhibitor; linagliptin; Langendorff; nitric oxide; ischemia reperfusion injury DPP-4 inhibitor; linagliptin; Langendorff; nitric oxide; ischemia reperfusion injury
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MDPI and ACS Style

Batchu, S.N.; Yerra, V.G.; Liu, Y.; Advani, S.L.; Klein, T.; Advani, A. The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Directly Enhances the Contractile Recovery of Mouse Hearts at a Concentration Equivalent to that Achieved with Standard Dosing in Humans. Int. J. Mol. Sci. 2020, 21, 5756. https://doi.org/10.3390/ijms21165756

AMA Style

Batchu SN, Yerra VG, Liu Y, Advani SL, Klein T, Advani A. The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Directly Enhances the Contractile Recovery of Mouse Hearts at a Concentration Equivalent to that Achieved with Standard Dosing in Humans. International Journal of Molecular Sciences. 2020; 21(16):5756. https://doi.org/10.3390/ijms21165756

Chicago/Turabian Style

Batchu, Sri N.; Yerra, Veera G.; Liu, Youan; Advani, Suzanne L.; Klein, Thomas; Advani, Andrew. 2020. "The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Directly Enhances the Contractile Recovery of Mouse Hearts at a Concentration Equivalent to that Achieved with Standard Dosing in Humans" Int. J. Mol. Sci. 21, no. 16: 5756. https://doi.org/10.3390/ijms21165756

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