Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension
Abstract Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We developed a novel “two-hit” model, w...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-024-84515-9 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841559567254683648 |
|---|---|
| author | Justin H. Berger Yuji Shi Timothy R. Matsuura Kirill Batmanov Xian Chen Kelly Tam Mackenzie Marshall Richard Kue Jiten Patel Renee Taing Russell Callaway Joanna Griffin Attila Kovacs Dinesh Hirenallur-Shanthappa Russell Miller Bei B. Zhang Rachel J. Roth Flach Daniel P. Kelly |
| author_facet | Justin H. Berger Yuji Shi Timothy R. Matsuura Kirill Batmanov Xian Chen Kelly Tam Mackenzie Marshall Richard Kue Jiten Patel Renee Taing Russell Callaway Joanna Griffin Attila Kovacs Dinesh Hirenallur-Shanthappa Russell Miller Bei B. Zhang Rachel J. Roth Flach Daniel P. Kelly |
| author_sort | Justin H. Berger |
| collection | DOAJ |
| description | Abstract Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We developed a novel “two-hit” model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57Bl6/NJ mice fed a high-fat diet (HFD) for > 10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d. HFD-Renin (aka “HFpEF”) mice demonstrated obesity and insulin resistance, moderate left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by echocardiographic measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to human HFpEF. Treatment with empagliflozin, an effective but incompletely understood HFpEF therapy, improved multiple endpoints. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Additional preclinical HFpEF models allow for orthogonal studies to increase validity in assessment of interventions. |
| format | Article |
| id | doaj-art-55f8f7dfdf724c7d9cda3fddaa0efab9 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-55f8f7dfdf724c7d9cda3fddaa0efab92025-01-05T12:22:56ZengNature PortfolioScientific Reports2045-23222025-01-0115111310.1038/s41598-024-84515-9Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertensionJustin H. Berger0Yuji Shi1Timothy R. Matsuura2Kirill Batmanov3Xian Chen4Kelly Tam5Mackenzie Marshall6Richard Kue7Jiten Patel8Renee Taing9Russell Callaway10Joanna Griffin11Attila Kovacs12Dinesh Hirenallur-Shanthappa13Russell Miller14Bei B. Zhang15Rachel J. Roth Flach16Daniel P. Kelly17Cardiovascular Institute, Children’s Hospital of PhiladelphiaInternal Medicine Research Unit, Pfizer Worldwide Research, Development & MedicalCardiovascular Institute, Perelman School of Medicine, University of PennsylvaniaCardiovascular Institute, Perelman School of Medicine, University of PennsylvaniaDepartment of Pediatrics, Washington University School of MedicineInternal Medicine Research Unit, Pfizer Worldwide Research, Development & MedicalInternal Medicine Research Unit, Pfizer Worldwide Research, Development & MedicalInternal Medicine Research Unit, Pfizer Worldwide Research, Development & MedicalCardiovascular Institute, Perelman School of Medicine, University of PennsylvaniaCardiovascular Institute, Perelman School of Medicine, University of PennsylvaniaCardiovascular Institute, Perelman School of Medicine, University of PennsylvaniaCardiovascular Institute, Perelman School of Medicine, University of PennsylvaniaDepartment of Medicine, Washington University School of MedicineInternal Medicine Research Unit, Pfizer Worldwide Research, Development & MedicalInternal Medicine Research Unit, Pfizer Worldwide Research, Development & MedicalInternal Medicine Research Unit, Pfizer Worldwide Research, Development & MedicalInternal Medicine Research Unit, Pfizer Worldwide Research, Development & MedicalCardiovascular Institute, Children’s Hospital of PhiladelphiaAbstract Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We developed a novel “two-hit” model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57Bl6/NJ mice fed a high-fat diet (HFD) for > 10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d. HFD-Renin (aka “HFpEF”) mice demonstrated obesity and insulin resistance, moderate left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by echocardiographic measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to human HFpEF. Treatment with empagliflozin, an effective but incompletely understood HFpEF therapy, improved multiple endpoints. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Additional preclinical HFpEF models allow for orthogonal studies to increase validity in assessment of interventions.https://doi.org/10.1038/s41598-024-84515-9Cardiovascular diseaseHeart failure with preserved ejection fractionMouse modelsDiastolic dysfunction |
| spellingShingle | Justin H. Berger Yuji Shi Timothy R. Matsuura Kirill Batmanov Xian Chen Kelly Tam Mackenzie Marshall Richard Kue Jiten Patel Renee Taing Russell Callaway Joanna Griffin Attila Kovacs Dinesh Hirenallur-Shanthappa Russell Miller Bei B. Zhang Rachel J. Roth Flach Daniel P. Kelly Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension Scientific Reports Cardiovascular disease Heart failure with preserved ejection fraction Mouse models Diastolic dysfunction |
| title | Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension |
| title_full | Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension |
| title_fullStr | Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension |
| title_full_unstemmed | Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension |
| title_short | Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension |
| title_sort | two hit mouse model of heart failure with preserved ejection fraction combining diet induced obesity and renin mediated hypertension |
| topic | Cardiovascular disease Heart failure with preserved ejection fraction Mouse models Diastolic dysfunction |
| url | https://doi.org/10.1038/s41598-024-84515-9 |
| work_keys_str_mv | AT justinhberger twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT yujishi twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT timothyrmatsuura twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT kirillbatmanov twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT xianchen twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT kellytam twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT mackenziemarshall twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT richardkue twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT jitenpatel twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT reneetaing twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT russellcallaway twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT joannagriffin twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT attilakovacs twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT dineshhirenallurshanthappa twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT russellmiller twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT beibzhang twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT racheljrothflach twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension AT danielpkelly twohitmousemodelofheartfailurewithpreservedejectionfractioncombiningdietinducedobesityandreninmediatedhypertension |