Insulin‐Like Growth Factor 1 Receptor Deficiency Alleviates Angiotensin II–Induced Cardiac Fibrosis Through the Protein Kinase B/Extracellular Signal‐Regulated Kinase/Nuclear Factor‐κB Pathway
Background The renin‐angiotensin system plays a crucial role in the development of heart failure, and Ang II (angiotensin II) acts as the critical effector of the renin‐angiotensin system in regulating cardiac fibrosis. However, the mechanisms of cardiac fibrosis are complex and still not fully unde...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-09-01
|
| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.123.029631 |
| _version_ | 1797632586812489728 |
|---|---|
| author | Jiafeng Zhu Qian Li Yan Sun Shiyu Zhang Ruiyan Pan Yanguang Xie Jinyan Chen Lihong Shi Yanbo Chen Zhipeng Sun Lane Zhang |
| author_facet | Jiafeng Zhu Qian Li Yan Sun Shiyu Zhang Ruiyan Pan Yanguang Xie Jinyan Chen Lihong Shi Yanbo Chen Zhipeng Sun Lane Zhang |
| author_sort | Jiafeng Zhu |
| collection | DOAJ |
| description | Background The renin‐angiotensin system plays a crucial role in the development of heart failure, and Ang II (angiotensin II) acts as the critical effector of the renin‐angiotensin system in regulating cardiac fibrosis. However, the mechanisms of cardiac fibrosis are complex and still not fully understood. IGF1R (insulin‐like growth factor 1 receptor) has multiple functions in maintaining cardiovascular homeostasis, and low‐dose IGF1 treatment is effective in relieving Ang II–induced cardiac fibrosis. Here, we aimed to investigate the molecular mechanism of IGF1R in Ang II–induced cardiac fibrosis. Methods and Results Using primary mouse cardiac microvascular endothelial cells and fibroblasts, in vitro experiments were performed. Using C57BL/6J mice and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated 9 (Cas9)‐mediated IGF1R heterozygous knockout (Igf1r+/−) mice, cardiac fibrosis mouse models were induced by Ang II for 2 weeks. The expression of IGF1R was examined by quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and Western blot. Mice heart histologic changes were evaluated using Masson and picro sirius red staining. Fibrotic markers and signal molecules indicating the function of the Akt (protein kinase B)/ERK (extracellular signal‐regulated kinase)/nuclear factor‐κB pathway were detected using quantitative reverse transcription polymerase chain reaction and Western blot. RNA sequencing was used to explore IGF1R‐mediated target genes in the hearts of mice, and the association of IGF1R and G‐protein–coupled receptor kinase 5 was identified by coimmunoprecipitation. More important, blocking IGF1R signaling significantly suppressed endothelial‐mesenchymal transition in primary mouse cardiac microvascular endothelial cells and mice in response to transforming growth factor‐β1 or Ang II, respectively. Deficiency or inhibition of IGF1R signaling remarkably attenuated Ang II–induced cardiac fibrosis in primary mouse cardiac fibroblasts and mice. We further observed that the patients with heart failure exhibited higher blood levels of IGF1 and IGF1R than healthy individuals. Moreover, Ang II treatment significantly increased cardiac IGF1R in wild type mice but led to a slight downregulation in Igf1r+/− mice. Interestingly, IGF1R deficiency significantly alleviated cardiac fibrosis in Ang II–treated mice. Mechanistically, the phosphorylation level of Akt and ERK was upregulated in Ang II–treated mice, whereas blocking IGF1R signaling in mice inhibited these changes of Akt and ERK phosphorylation. Concurrently, phosphorylated p65 of nuclear factor‐κB exhibited similar alterations in the corresponding group of mice. Intriguingly, IGF1R directly interacted with G‐protein–coupled receptor kinase 5, and this association decreased ≈50% in Igf1r+/− mice. In addition, Grk5 deletion downregulated expression of the Akt/ERK/nuclear factor‐κB signaling pathway in primary mouse cardiac fibroblasts. Conclusions IGF1R signaling deficiency alleviates Ang II–induced cardiac fibrosis, at least partially through inhibiting endothelial‐mesenchymal transition via the Akt/ERK/nuclear factor‐κB pathway. Interestingly, G‐protein–coupled receptor kinase 5 associates with IGF1R signaling directly, and it concurrently acts as an IGF1R downstream effector. This study suggests the promising potential of IGF1R as a therapeutic target for cardiac fibrosis. |
| first_indexed | 2024-03-11T11:39:01Z |
| format | Article |
| id | doaj.art-d07dbc7d7f9149f29cb0aa84cc35747b |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-11T11:39:01Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-d07dbc7d7f9149f29cb0aa84cc35747b2023-11-10T10:23:41ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802023-09-01121810.1161/JAHA.123.029631Insulin‐Like Growth Factor 1 Receptor Deficiency Alleviates Angiotensin II–Induced Cardiac Fibrosis Through the Protein Kinase B/Extracellular Signal‐Regulated Kinase/Nuclear Factor‐κB PathwayJiafeng Zhu0Qian Li1Yan Sun2Shiyu Zhang3Ruiyan Pan4Yanguang Xie5Jinyan Chen6Lihong Shi7Yanbo Chen8Zhipeng Sun9Lane Zhang10Department of Nursing Weifang Medical University Weifang ChinaDepartment of Nursing Weifang Medical University Weifang ChinaDepartment of Stomatology Weifang Medical University Weifang ChinaDepartment of Nursing Weifang Medical University Weifang ChinaDepartment of Pharmacology Weifang Medical University Weifang ChinaDepartment of Nursing Weifang Medical University Weifang ChinaDepartment of Clinical Medicine Weifang Medical University Weifang ChinaDepartment of Rehabilitation Medicine Weifang Medical University Weifang ChinaDepartment of Cardiology, The First Affiliated Hospital Weifang Medical University Weifang ChinaDepartment of Pharmacology Weifang Medical University Weifang ChinaDepartment of Nursing Weifang Medical University Weifang ChinaBackground The renin‐angiotensin system plays a crucial role in the development of heart failure, and Ang II (angiotensin II) acts as the critical effector of the renin‐angiotensin system in regulating cardiac fibrosis. However, the mechanisms of cardiac fibrosis are complex and still not fully understood. IGF1R (insulin‐like growth factor 1 receptor) has multiple functions in maintaining cardiovascular homeostasis, and low‐dose IGF1 treatment is effective in relieving Ang II–induced cardiac fibrosis. Here, we aimed to investigate the molecular mechanism of IGF1R in Ang II–induced cardiac fibrosis. Methods and Results Using primary mouse cardiac microvascular endothelial cells and fibroblasts, in vitro experiments were performed. Using C57BL/6J mice and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated 9 (Cas9)‐mediated IGF1R heterozygous knockout (Igf1r+/−) mice, cardiac fibrosis mouse models were induced by Ang II for 2 weeks. The expression of IGF1R was examined by quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and Western blot. Mice heart histologic changes were evaluated using Masson and picro sirius red staining. Fibrotic markers and signal molecules indicating the function of the Akt (protein kinase B)/ERK (extracellular signal‐regulated kinase)/nuclear factor‐κB pathway were detected using quantitative reverse transcription polymerase chain reaction and Western blot. RNA sequencing was used to explore IGF1R‐mediated target genes in the hearts of mice, and the association of IGF1R and G‐protein–coupled receptor kinase 5 was identified by coimmunoprecipitation. More important, blocking IGF1R signaling significantly suppressed endothelial‐mesenchymal transition in primary mouse cardiac microvascular endothelial cells and mice in response to transforming growth factor‐β1 or Ang II, respectively. Deficiency or inhibition of IGF1R signaling remarkably attenuated Ang II–induced cardiac fibrosis in primary mouse cardiac fibroblasts and mice. We further observed that the patients with heart failure exhibited higher blood levels of IGF1 and IGF1R than healthy individuals. Moreover, Ang II treatment significantly increased cardiac IGF1R in wild type mice but led to a slight downregulation in Igf1r+/− mice. Interestingly, IGF1R deficiency significantly alleviated cardiac fibrosis in Ang II–treated mice. Mechanistically, the phosphorylation level of Akt and ERK was upregulated in Ang II–treated mice, whereas blocking IGF1R signaling in mice inhibited these changes of Akt and ERK phosphorylation. Concurrently, phosphorylated p65 of nuclear factor‐κB exhibited similar alterations in the corresponding group of mice. Intriguingly, IGF1R directly interacted with G‐protein–coupled receptor kinase 5, and this association decreased ≈50% in Igf1r+/− mice. In addition, Grk5 deletion downregulated expression of the Akt/ERK/nuclear factor‐κB signaling pathway in primary mouse cardiac fibroblasts. Conclusions IGF1R signaling deficiency alleviates Ang II–induced cardiac fibrosis, at least partially through inhibiting endothelial‐mesenchymal transition via the Akt/ERK/nuclear factor‐κB pathway. Interestingly, G‐protein–coupled receptor kinase 5 associates with IGF1R signaling directly, and it concurrently acts as an IGF1R downstream effector. This study suggests the promising potential of IGF1R as a therapeutic target for cardiac fibrosis.https://www.ahajournals.org/doi/10.1161/JAHA.123.029631angiotensin IIcardiac fibrosisG‐protein–coupled receptor kinase 5insulin‐like growth factor 1 receptorprotein kinase B/extracellular signal‐regulated kinase/nuclear factor‐κB pathway |
| spellingShingle | Jiafeng Zhu Qian Li Yan Sun Shiyu Zhang Ruiyan Pan Yanguang Xie Jinyan Chen Lihong Shi Yanbo Chen Zhipeng Sun Lane Zhang Insulin‐Like Growth Factor 1 Receptor Deficiency Alleviates Angiotensin II–Induced Cardiac Fibrosis Through the Protein Kinase B/Extracellular Signal‐Regulated Kinase/Nuclear Factor‐κB Pathway Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease angiotensin II cardiac fibrosis G‐protein–coupled receptor kinase 5 insulin‐like growth factor 1 receptor protein kinase B/extracellular signal‐regulated kinase/nuclear factor‐κB pathway |
| title | Insulin‐Like Growth Factor 1 Receptor Deficiency Alleviates Angiotensin II–Induced Cardiac Fibrosis Through the Protein Kinase B/Extracellular Signal‐Regulated Kinase/Nuclear Factor‐κB Pathway |
| title_full | Insulin‐Like Growth Factor 1 Receptor Deficiency Alleviates Angiotensin II–Induced Cardiac Fibrosis Through the Protein Kinase B/Extracellular Signal‐Regulated Kinase/Nuclear Factor‐κB Pathway |
| title_fullStr | Insulin‐Like Growth Factor 1 Receptor Deficiency Alleviates Angiotensin II–Induced Cardiac Fibrosis Through the Protein Kinase B/Extracellular Signal‐Regulated Kinase/Nuclear Factor‐κB Pathway |
| title_full_unstemmed | Insulin‐Like Growth Factor 1 Receptor Deficiency Alleviates Angiotensin II–Induced Cardiac Fibrosis Through the Protein Kinase B/Extracellular Signal‐Regulated Kinase/Nuclear Factor‐κB Pathway |
| title_short | Insulin‐Like Growth Factor 1 Receptor Deficiency Alleviates Angiotensin II–Induced Cardiac Fibrosis Through the Protein Kinase B/Extracellular Signal‐Regulated Kinase/Nuclear Factor‐κB Pathway |
| title_sort | insulin like growth factor 1 receptor deficiency alleviates angiotensin ii induced cardiac fibrosis through the protein kinase b extracellular signal regulated kinase nuclear factor κb pathway |
| topic | angiotensin II cardiac fibrosis G‐protein–coupled receptor kinase 5 insulin‐like growth factor 1 receptor protein kinase B/extracellular signal‐regulated kinase/nuclear factor‐κB pathway |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.123.029631 |
| work_keys_str_mv | AT jiafengzhu insulinlikegrowthfactor1receptordeficiencyalleviatesangiotensiniiinducedcardiacfibrosisthroughtheproteinkinasebextracellularsignalregulatedkinasenuclearfactorkbpathway AT qianli insulinlikegrowthfactor1receptordeficiencyalleviatesangiotensiniiinducedcardiacfibrosisthroughtheproteinkinasebextracellularsignalregulatedkinasenuclearfactorkbpathway AT yansun insulinlikegrowthfactor1receptordeficiencyalleviatesangiotensiniiinducedcardiacfibrosisthroughtheproteinkinasebextracellularsignalregulatedkinasenuclearfactorkbpathway AT shiyuzhang insulinlikegrowthfactor1receptordeficiencyalleviatesangiotensiniiinducedcardiacfibrosisthroughtheproteinkinasebextracellularsignalregulatedkinasenuclearfactorkbpathway AT ruiyanpan insulinlikegrowthfactor1receptordeficiencyalleviatesangiotensiniiinducedcardiacfibrosisthroughtheproteinkinasebextracellularsignalregulatedkinasenuclearfactorkbpathway AT yanguangxie insulinlikegrowthfactor1receptordeficiencyalleviatesangiotensiniiinducedcardiacfibrosisthroughtheproteinkinasebextracellularsignalregulatedkinasenuclearfactorkbpathway AT jinyanchen insulinlikegrowthfactor1receptordeficiencyalleviatesangiotensiniiinducedcardiacfibrosisthroughtheproteinkinasebextracellularsignalregulatedkinasenuclearfactorkbpathway AT lihongshi insulinlikegrowthfactor1receptordeficiencyalleviatesangiotensiniiinducedcardiacfibrosisthroughtheproteinkinasebextracellularsignalregulatedkinasenuclearfactorkbpathway AT yanbochen insulinlikegrowthfactor1receptordeficiencyalleviatesangiotensiniiinducedcardiacfibrosisthroughtheproteinkinasebextracellularsignalregulatedkinasenuclearfactorkbpathway AT zhipengsun insulinlikegrowthfactor1receptordeficiencyalleviatesangiotensiniiinducedcardiacfibrosisthroughtheproteinkinasebextracellularsignalregulatedkinasenuclearfactorkbpathway AT lanezhang insulinlikegrowthfactor1receptordeficiencyalleviatesangiotensiniiinducedcardiacfibrosisthroughtheproteinkinasebextracellularsignalregulatedkinasenuclearfactorkbpathway |