Linagliptin prevents left ventricular stiffening by reducing titin cleavage and hypophosphorylation

Cuijpers, Ilona; Papageorgiou, Anna-Pia; Carai, Paolo; Herwig, Melissa; Mügge, Andreas; Klein, Thomas; Hamdani, Nazha; Jones, Elizabeth A. V.; Heymans, Stéphane

doi:10.1111/jcmm.16122

Cited by 7 publications

(6 citation statements)

References 56 publications

(127 reference statements)

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“…CD26/DPP4 in cardiac tissue is mainly expressed on the surface of vascular endothelial cells of the coronary capillaries as well as in infiltrating immune cells (Cuijpers et al, 2021; Iwanaga & Nio‐Kobayashi, 2021). Cytosolic expression of CD26/DPP4 was further observed in some cardiomyocytes (Cuijpers et al, 2021).…”

Section: Evidence To Repurpose Pharmacological Cd26/dpp4 Inhibition I...mentioning

confidence: 99%

“…Several preclinical studies in rats, mice and rabbits have evaluated the effect of pharmacological CD26/DPP4 inhibition in cardiac injury caused by experimental diabetes or hypertension without additional surgically induced cardiac impairment. These studies uniformly describe a cardioprotective effect of CD26/DPP4 inhibition resulting in a reduction of histological perivascular and interstitial fibrosis, prevention of diastolic dysfunction and preserved left ventricular compliance (Cuijpers et al, 2021; Esposito et al, 2017; Shigeta et al, 2012; Yamamoto et al, 2018; Zhang et al, 2018).…”

Section: Evidence To Repurpose Pharmacological Cd26/dpp4 Inhibition I...mentioning

confidence: 99%

“…Additional myofibroblast progenitors can be recruited from the periphery, as bone marrow-derived fibrocytes contribute to scar formation after myocardial infarction (van Amerongen et al, 2008). CD26/DPP4 in cardiac tissue is mainly expressed on the surface of vascular endothelial cells of the coronary capillaries as well as in infiltrating immune cells (Cuijpers et al, 2021;Iwanaga & Nio-Kobayashi, 2021). Cytosolic expression of CD26/DPP4 was further observed in some cardiomyocytes (Cuijpers et al, 2021).…”

Section: Cardiomyopathy Myocardial Infarction and Heart Failurementioning

confidence: 99%

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Targeting cluster of differentiation 26 / dipeptidyl peptidase 4 (CD26/DPP4) in organ fibrosis

Ohm

Moneke

Jungraithmayr

2022

British J Pharmacology

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Cluster of differentiation 26 (CD26)/dipeptidyl peptidase 4 (DPP4) is an exopeptidase that is expressed as a transmembrane protein in many organs but also present in a circulating soluble form. Beyond its enzymatic and costimulatory activity, CD26/DPP4 is involved in the pathogenesis of chronic fibrotic diseases across many organ types, such as liver cirrhosis, kidney fibrosis and lung fibrosis. Organ fibrosis is associated with a high morbidity and mortality, and there are no causative therapies that can effectively attenuate the progress of the disease. Growing evidence suggests that inhibiting CD26/DPP4 can modulate the profibrotic tissue microenvironment and thus reduce fibrotic changes within affected organs. This review summarizes the role of CD26/DPP4 in fibroproliferative disorders and highlights new opportunities for an antifibrotic treatment by CD26/DPP4 inhibition. As a major advantage, CD26/DPP4 inhibitors have been in safe and routine clinical use in type 2 diabetes for many years and thus qualify for repurposing to repurpose as a promising therapeutic against fibrosis.

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Section: Evidence To Repurpose Pharmacological Cd26/dpp4 Inhibition I...mentioning

confidence: 99%

Section: Evidence To Repurpose Pharmacological Cd26/dpp4 Inhibition I...mentioning

confidence: 99%

Section: Cardiomyopathy Myocardial Infarction and Heart Failurementioning

confidence: 99%

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Targeting cluster of differentiation 26 / dipeptidyl peptidase 4 (CD26/DPP4) in organ fibrosis

Ohm

Moneke

Jungraithmayr

2022

British J Pharmacology

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“… 122 The ZSF1‐Ob rat model has been shown to have significant increases in left ventricular mass, left ventricular wall thickness, and left ventricular end‐diastolic diameter as early as 20 weeks, along with diastolic dysfunction. 53 Prominent cardiac features include altered titin isoform expression and/or posttranslational modification, 8 , 123 , 124 impaired NO/cGMP/PKG signaling 124 , 125 , 126 and Ca 2+ handling, 8 , 127 , 128 and mitochondrial dysfunction. 127 , 128 Cardiac fibrosis would seem to be a less prominent feature of this model.…”

Section: Conventional Preclinical Modelsmentioning

confidence: 99%

Genomic, Proteomic, and Metabolic Comparisons of Small Animal Models of Heart Failure With Preserved Ejection Fraction: A Tale of Mice, Rats, and Cats

Smith

Altara

Amin

et al. 2022

JAHA

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Heart failure with preserved ejection fraction (HFpEF) remains a medical anomaly that baffles researchers and physicians alike. The overall phenotypical changes of diastolic function and left ventricular hypertrophy observed in HFpEF are definable; however, the metabolic and molecular alterations that ultimately produce these changes are not well established. Comorbidities such as obesity, hypertension, and diabetes, as well as general aging, play crucial roles in its development and progression. Various animal models have recently been developed to better understand the pathophysiological and metabolic developments in HFpEF and to illuminate novel avenues for pharmacotherapy. These models include multi‐hit rodents and feline aortic constriction animals. Recently, genomic, proteomic, and metabolomic approaches have been used to define altered signaling pathways in the heart associated with HFpEF, including those involved in inflammation, cGMP‐related, Ca 2+ handling, mitochondrial respiration, and the unfolded protein response in endoplasmic reticulum stress. This article aims to present an overview of what has been learnt by these studies, focusing mainly on the findings in common while highlighting unresolved issues. The knowledge gained from these research models will not simply be of benefit for treating HFpEF but will undoubtedly provide new insights into the mechanisms by which the heart deals with external stresses and how the processes involved can fail.

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“…EndMT is also relevant in cardiac fibrosis, a common pathological condition in both type 1 and type 2 diabetes patients 8 , 9 , 10 . Linagliptin has been shown to prevent left ventricular stiffening, which lessens titin protein degradation and hypophosphorylation in diabetic hearts 11 . Furthermore, linagliptin has been shown to suppress angiotensin II type 1 receptor expression and angiotensin II‐induced cardiac fibrosis 12 .…”

Section: Introductionmentioning

confidence: 99%

Linagliptin ameliorated cardiac fibrosis and restored cardiomyocyte structure in diabetic mice associated with the suppression of necroptosis

Adhikari

Hirai

Kawakita

et al. 2023

J of Diabetes Invest

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Aims/Introduction Linagliptin is a selective dipeptidyl peptidase (DPP)‐4 inhibitor capable of successfully regulating blood glucose levels. The cardiovascular protective effects of several DPP‐4 inhibitors have been shown in preclinical studies; however, the detailed influence of DPP‐4 inhibitors on diabetic pathological alterations in cardiac tissue has not yet been elucidated. Materials and Methods We combined laboratory‐based experiments and bioinformatics techniques to identify suitable candidate targets with significant biological pathways. Mice with streptozotocin‐induced insulin deficiency diabetic model were utilized for in vivo experiments. Mice were euthanized at 24 weeks after the induction of diabetes; linagliptin intervention was carried out for 4 weeks before euthanasia. Microarray analysis of heart samples was carried out. Results Mice with streptozotocin‐induced diabetes, but not control mice, showed cardiac fibrosis with an endothelial–mesenchymal transition program, and myocardial fiber and sarcomere disruption; linagliptin alleviated these diabetes‐associated pathological alterations without altering blood glucose levels. Bioinformatics analysis utilizing a microarray dataset identified 10 hub genes that were confirmed to have human disease relevance by Gene Expression Omnibus analysis. Among these hub genes, we focused on the Sox9–necroptosis axis as a therapeutic target in diabetic hearts. Indeed, diabetic mice showed the induction of necroptosis‐associated genes and the phosphorylation of RIP3 and mixed lineage kinase domain‐like protein. Conclusions Linagliptin showed excellent heart protection in mice with streptozotocin‐induced diabetes associated with alterations in human disease‐relevant hub genes. Further investigation is required to determine why DPP‐4 inhibitors do not show similar superior organ‐protective effects in the clinical setting.

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Linagliptin prevents left ventricular stiffening by reducing titin cleavage and hypophosphorylation

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 7 publications

References 56 publications

Targeting cluster of differentiation 26 / dipeptidyl peptidase 4 (CD26/DPP4) in organ fibrosis

Targeting cluster of differentiation 26 / dipeptidyl peptidase 4 (CD26/DPP4) in organ fibrosis

Genomic, Proteomic, and Metabolic Comparisons of Small Animal Models of Heart Failure With Preserved Ejection Fraction: A Tale of Mice, Rats, and Cats

Linagliptin ameliorated cardiac fibrosis and restored cardiomyocyte structure in diabetic mice associated with the suppression of necroptosis

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