Interleukin‐1β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction Pathogenesis
Background Heart failure with preserved ejection fraction (HFpEF) is a significant unmet need in cardiovascular medicine and remains an untreatable cardiovascular disease. The role and mechanism of interleukin‐1β in HFpEF pathogenesis are poorly understood. Methods and Results C57/Bl6J and interleuk...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-07-01
|
| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.122.029668 |
| _version_ | 1828718396542287872 |
|---|---|
| author | Balaji K. Srinivas Aya Bourdi Jacob D. O'Regan Kumar D. Malavalli Nour‐Eddine Rhaleb Souad Belmadani Khalid Matrougui |
| author_facet | Balaji K. Srinivas Aya Bourdi Jacob D. O'Regan Kumar D. Malavalli Nour‐Eddine Rhaleb Souad Belmadani Khalid Matrougui |
| author_sort | Balaji K. Srinivas |
| collection | DOAJ |
| description | Background Heart failure with preserved ejection fraction (HFpEF) is a significant unmet need in cardiovascular medicine and remains an untreatable cardiovascular disease. The role and mechanism of interleukin‐1β in HFpEF pathogenesis are poorly understood. Methods and Results C57/Bl6J and interleukin‐1β−/− male mice were randomly divided into 4 groups. Groups 1 and 2: C57/Bl6J and interleukin‐1β−/− mice were fed a regular diet for 4 months and considered controls. Groups 3 and 4: C57/Bl6 and interleukin‐1β−/− mice were fed a high‐fat diet with N[w]‐nitro‐l‐arginine methyl ester (endothelial nitric oxide synthase inhibitor, 0.5 g/L) in the drinking water for 4 months. We measured body weight, blood pressure, diabetes status, cardiac function/hypertrophy/inflammation, fibrosis, vascular endothelial function, and signaling. C57/Bl6 fed a high‐fat diet and N[w]‐nitro‐l‐arginine methyl ester in the drinking water for 4 months developed HFpEF pathogenesis characterized by obesity, diabetes, hypertension, cardiac hypertrophy, lung edema, low running performance, macrovascular and microvascular endothelial dysfunction, and diastolic cardiac dysfunction but no change in cardiac ejection fraction compared with control mice. Interestingly, the genetic disruption of interleukin‐1β protected mice from HFpEF pathogenesis through the modulation of the inflammation and endoplasmic reticulum stress mechanisms. Conclusions Our data suggest that interleukin‐1β is a critical driver in the development of HFpEF pathogenesis, likely through regulating inflammation and endoplasmic reticulum stress pathways. Our findings provide a potential therapeutic target for HFpEF treatment. |
| first_indexed | 2024-03-12T14:43:06Z |
| format | Article |
| id | doaj.art-8596badf93e948aca778f95610bd30c8 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-12T14:43:06Z |
| publishDate | 2023-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-8596badf93e948aca778f95610bd30c82023-08-16T04:54:44ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802023-07-01121410.1161/JAHA.122.029668Interleukin‐1β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction PathogenesisBalaji K. Srinivas0Aya Bourdi1Jacob D. O'Regan2Kumar D. Malavalli3Nour‐Eddine Rhaleb4Souad Belmadani5Khalid Matrougui6Department of Physiological Sciences EVMS Norfolk VA USADepartment of Physiological Sciences EVMS Norfolk VA USADepartment of Physiological Sciences EVMS Norfolk VA USADepartment of Physiological Sciences EVMS Norfolk VA USAHypertension & Vascular Research Division Department of Internal Medicine Henry Ford Health Detroit MI USADepartment of Physiological Sciences EVMS Norfolk VA USADepartment of Physiological Sciences EVMS Norfolk VA USABackground Heart failure with preserved ejection fraction (HFpEF) is a significant unmet need in cardiovascular medicine and remains an untreatable cardiovascular disease. The role and mechanism of interleukin‐1β in HFpEF pathogenesis are poorly understood. Methods and Results C57/Bl6J and interleukin‐1β−/− male mice were randomly divided into 4 groups. Groups 1 and 2: C57/Bl6J and interleukin‐1β−/− mice were fed a regular diet for 4 months and considered controls. Groups 3 and 4: C57/Bl6 and interleukin‐1β−/− mice were fed a high‐fat diet with N[w]‐nitro‐l‐arginine methyl ester (endothelial nitric oxide synthase inhibitor, 0.5 g/L) in the drinking water for 4 months. We measured body weight, blood pressure, diabetes status, cardiac function/hypertrophy/inflammation, fibrosis, vascular endothelial function, and signaling. C57/Bl6 fed a high‐fat diet and N[w]‐nitro‐l‐arginine methyl ester in the drinking water for 4 months developed HFpEF pathogenesis characterized by obesity, diabetes, hypertension, cardiac hypertrophy, lung edema, low running performance, macrovascular and microvascular endothelial dysfunction, and diastolic cardiac dysfunction but no change in cardiac ejection fraction compared with control mice. Interestingly, the genetic disruption of interleukin‐1β protected mice from HFpEF pathogenesis through the modulation of the inflammation and endoplasmic reticulum stress mechanisms. Conclusions Our data suggest that interleukin‐1β is a critical driver in the development of HFpEF pathogenesis, likely through regulating inflammation and endoplasmic reticulum stress pathways. Our findings provide a potential therapeutic target for HFpEF treatment.https://www.ahajournals.org/doi/10.1161/JAHA.122.029668cardiac fibrosisER stressHFpEFinflammationinterleukin‐1βvascular endothelial function |
| spellingShingle | Balaji K. Srinivas Aya Bourdi Jacob D. O'Regan Kumar D. Malavalli Nour‐Eddine Rhaleb Souad Belmadani Khalid Matrougui Interleukin‐1β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction Pathogenesis Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease cardiac fibrosis ER stress HFpEF inflammation interleukin‐1β vascular endothelial function |
| title | Interleukin‐1β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction Pathogenesis |
| title_full | Interleukin‐1β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction Pathogenesis |
| title_fullStr | Interleukin‐1β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction Pathogenesis |
| title_full_unstemmed | Interleukin‐1β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction Pathogenesis |
| title_short | Interleukin‐1β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction Pathogenesis |
| title_sort | interleukin 1β disruption protects male mice from heart failure with preserved ejection fraction pathogenesis |
| topic | cardiac fibrosis ER stress HFpEF inflammation interleukin‐1β vascular endothelial function |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.122.029668 |
| work_keys_str_mv | AT balajiksrinivas interleukin1bdisruptionprotectsmalemicefromheartfailurewithpreservedejectionfractionpathogenesis AT ayabourdi interleukin1bdisruptionprotectsmalemicefromheartfailurewithpreservedejectionfractionpathogenesis AT jacobdoregan interleukin1bdisruptionprotectsmalemicefromheartfailurewithpreservedejectionfractionpathogenesis AT kumardmalavalli interleukin1bdisruptionprotectsmalemicefromheartfailurewithpreservedejectionfractionpathogenesis AT noureddinerhaleb interleukin1bdisruptionprotectsmalemicefromheartfailurewithpreservedejectionfractionpathogenesis AT souadbelmadani interleukin1bdisruptionprotectsmalemicefromheartfailurewithpreservedejectionfractionpathogenesis AT khalidmatrougui interleukin1bdisruptionprotectsmalemicefromheartfailurewithpreservedejectionfractionpathogenesis |