Elimination of hepatocyte‐derived DPP4 downregulates cardiac immune‐ and collagen‐related genes but does not alter cardiac function in aged male mice
Abstract The association between metabolic dysfunction–associated steatotic liver disease (MASLD) and cardiovascular disease is well characterized; however, the underlying mechanism is incompletely understood. Interestingly, hepatocyte‐specific silencing of dipeptidyl peptidase 4 (DPP4) prevents liv...
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Wiley
2025-08-01
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| Series: | Physiological Reports |
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| Online Access: | https://doi.org/10.14814/phy2.70453 |
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| author | Natasha A. Trzaskalski Melissa M. Dann Antonio Hanson Branka Vulesevic Evgenia Fadzeyeva Natasha Jeraj Ilka Lorenzen‐Schmidt Rick Seymour Erin E. Mulvihill |
| author_facet | Natasha A. Trzaskalski Melissa M. Dann Antonio Hanson Branka Vulesevic Evgenia Fadzeyeva Natasha Jeraj Ilka Lorenzen‐Schmidt Rick Seymour Erin E. Mulvihill |
| author_sort | Natasha A. Trzaskalski |
| collection | DOAJ |
| description | Abstract The association between metabolic dysfunction–associated steatotic liver disease (MASLD) and cardiovascular disease is well characterized; however, the underlying mechanism is incompletely understood. Interestingly, hepatocyte‐specific silencing of dipeptidyl peptidase 4 (DPP4) prevents liver fibrosis and adipose tissue inflammation; however, how this affects the heart remains to be investigated. This study evaluates how diastolic function and molecular signatures of heart failure, like inflammation and fibrosis, are affected in male Dpp4+/+, Dpp4−/−, and Dpp4flox/flox mice injected with a TBG‐CRE to selectively eliminate DPP4 from hepatocytes (Dpp4hep−/−) and respective controls (Dpp4GFP), aged and fed an HFHC diet for 24 weeks. Mice underwent pulsed‐wave and tissue Doppler echocardiography. Further, speckle‐tracking strain analysis was performed to detect diastolic dysfunction. Differential mRNA analysis using the NanoString platform and qRT‐PCR were conducted using ventricular tissue to assess immunological pathway expression, as well as hypertrophy, modeling‐related, senescence, and metabolism gene expression. Immunological pathway analysis of ventricular tissue revealed downregulation of 12 immune‐related pathways in Dpp4hep−/− mice, including apoptosis and chemokine and cytokine signaling; however, this was not observed in Dpp4−/− mice. Further, fibrosis and ECM modeling‐related genes, Col1a1, Col3a1, Ctgf, and Myh7, were significantly upregulated in Dpp4−/− mice but unchanged in Dpp4hep−/− mice, compared to controls. Interestingly, cardiac hypertrophy and systolic and diastolic function evaluated with echocardiography were unchanged. Immune‐related pathways are downregulated in Dpp4hep−/− mice, while fibrosis genes are significantly upregulated in Dpp4−/− mice, compared to respective controls. Despite these molecular changes, cardiac hypertrophy and systolic and diastolic function were unchanged with systemic and organ‐specific loss of Dpp4. |
| format | Article |
| id | doaj-art-7bd9b95f0ca344cab35aadfcd535a47f |
| institution | Kabale University |
| issn | 2051-817X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj-art-7bd9b95f0ca344cab35aadfcd535a47f2025-08-20T03:46:58ZengWileyPhysiological Reports2051-817X2025-08-011315n/an/a10.14814/phy2.70453Elimination of hepatocyte‐derived DPP4 downregulates cardiac immune‐ and collagen‐related genes but does not alter cardiac function in aged male miceNatasha A. Trzaskalski0Melissa M. Dann1Antonio Hanson2Branka Vulesevic3Evgenia Fadzeyeva4Natasha Jeraj5Ilka Lorenzen‐Schmidt6Rick Seymour7Erin E. Mulvihill8Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine The University of Ottawa Ottawa Ontario CanadaDepartment of Biochemistry, Microbiology and Immunology, Faculty of Medicine The University of Ottawa Ottawa Ontario CanadaDepartment of Biochemistry, Microbiology and Immunology, Faculty of Medicine The University of Ottawa Ottawa Ontario CanadaDepartment of Biochemistry, Microbiology and Immunology, Faculty of Medicine The University of Ottawa Ottawa Ontario CanadaDepartment of Biochemistry, Microbiology and Immunology, Faculty of Medicine The University of Ottawa Ottawa Ontario CanadaDepartment of Biochemistry, Microbiology and Immunology, Faculty of Medicine The University of Ottawa Ottawa Ontario CanadaThe University of Ottawa Heart Institute Ottawa Ontario CanadaThe University of Ottawa Heart Institute Ottawa Ontario CanadaDepartment of Biochemistry, Microbiology and Immunology, Faculty of Medicine The University of Ottawa Ottawa Ontario CanadaAbstract The association between metabolic dysfunction–associated steatotic liver disease (MASLD) and cardiovascular disease is well characterized; however, the underlying mechanism is incompletely understood. Interestingly, hepatocyte‐specific silencing of dipeptidyl peptidase 4 (DPP4) prevents liver fibrosis and adipose tissue inflammation; however, how this affects the heart remains to be investigated. This study evaluates how diastolic function and molecular signatures of heart failure, like inflammation and fibrosis, are affected in male Dpp4+/+, Dpp4−/−, and Dpp4flox/flox mice injected with a TBG‐CRE to selectively eliminate DPP4 from hepatocytes (Dpp4hep−/−) and respective controls (Dpp4GFP), aged and fed an HFHC diet for 24 weeks. Mice underwent pulsed‐wave and tissue Doppler echocardiography. Further, speckle‐tracking strain analysis was performed to detect diastolic dysfunction. Differential mRNA analysis using the NanoString platform and qRT‐PCR were conducted using ventricular tissue to assess immunological pathway expression, as well as hypertrophy, modeling‐related, senescence, and metabolism gene expression. Immunological pathway analysis of ventricular tissue revealed downregulation of 12 immune‐related pathways in Dpp4hep−/− mice, including apoptosis and chemokine and cytokine signaling; however, this was not observed in Dpp4−/− mice. Further, fibrosis and ECM modeling‐related genes, Col1a1, Col3a1, Ctgf, and Myh7, were significantly upregulated in Dpp4−/− mice but unchanged in Dpp4hep−/− mice, compared to controls. Interestingly, cardiac hypertrophy and systolic and diastolic function evaluated with echocardiography were unchanged. Immune‐related pathways are downregulated in Dpp4hep−/− mice, while fibrosis genes are significantly upregulated in Dpp4−/− mice, compared to respective controls. Despite these molecular changes, cardiac hypertrophy and systolic and diastolic function were unchanged with systemic and organ‐specific loss of Dpp4.https://doi.org/10.14814/phy2.70453cardiovascular dysfunctiondiastolic dysfunctiondipeptidyl peptidase‐4echocardiographyhepatokine |
| spellingShingle | Natasha A. Trzaskalski Melissa M. Dann Antonio Hanson Branka Vulesevic Evgenia Fadzeyeva Natasha Jeraj Ilka Lorenzen‐Schmidt Rick Seymour Erin E. Mulvihill Elimination of hepatocyte‐derived DPP4 downregulates cardiac immune‐ and collagen‐related genes but does not alter cardiac function in aged male mice Physiological Reports cardiovascular dysfunction diastolic dysfunction dipeptidyl peptidase‐4 echocardiography hepatokine |
| title | Elimination of hepatocyte‐derived DPP4 downregulates cardiac immune‐ and collagen‐related genes but does not alter cardiac function in aged male mice |
| title_full | Elimination of hepatocyte‐derived DPP4 downregulates cardiac immune‐ and collagen‐related genes but does not alter cardiac function in aged male mice |
| title_fullStr | Elimination of hepatocyte‐derived DPP4 downregulates cardiac immune‐ and collagen‐related genes but does not alter cardiac function in aged male mice |
| title_full_unstemmed | Elimination of hepatocyte‐derived DPP4 downregulates cardiac immune‐ and collagen‐related genes but does not alter cardiac function in aged male mice |
| title_short | Elimination of hepatocyte‐derived DPP4 downregulates cardiac immune‐ and collagen‐related genes but does not alter cardiac function in aged male mice |
| title_sort | elimination of hepatocyte derived dpp4 downregulates cardiac immune and collagen related genes but does not alter cardiac function in aged male mice |
| topic | cardiovascular dysfunction diastolic dysfunction dipeptidyl peptidase‐4 echocardiography hepatokine |
| url | https://doi.org/10.14814/phy2.70453 |
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