IP3 receptor orchestrates maladaptive vascular responses in heart failure
Patients with heart failure (HF) have augmented vascular tone, which increases cardiac workload, impairing ventricular output and promoting further myocardial dysfunction. The molecular mechanisms underlying the maladaptive vascular responses observed in HF are not fully understood. Vascular smooth...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-02-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI152859 |
| _version_ | 1811229869988642816 |
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| author | Haikel Dridi Gaetano Santulli Jessica Gambardella Stanislovas S. Jankauskas Qi Yuan Jingyi Yang Steven Reiken Xujun Wang Anetta Wronska Xiaoping Liu Alain Lacampagne Andrew R. Marks |
| author_facet | Haikel Dridi Gaetano Santulli Jessica Gambardella Stanislovas S. Jankauskas Qi Yuan Jingyi Yang Steven Reiken Xujun Wang Anetta Wronska Xiaoping Liu Alain Lacampagne Andrew R. Marks |
| author_sort | Haikel Dridi |
| collection | DOAJ |
| description | Patients with heart failure (HF) have augmented vascular tone, which increases cardiac workload, impairing ventricular output and promoting further myocardial dysfunction. The molecular mechanisms underlying the maladaptive vascular responses observed in HF are not fully understood. Vascular smooth muscle cells (VSMCs) control vasoconstriction via a Ca2+-dependent process, in which the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) on the sarcoplasmic reticulum (SR) plays a major role. To dissect the mechanistic contribution of intracellular Ca2+ release to the increased vascular tone observed in HF, we analyzed the remodeling of IP3R1 in aortic tissues from patients with HF and from controls. VSMC IP3R1 channels from patients with HF and HF mice were hyperphosphorylated by both serine and tyrosine kinases. VSMCs isolated from IP3R1VSMC–/– mice exhibited blunted Ca2+ responses to angiotensin II (ATII) and norepinephrine compared with control VSMCs. IP3R1VSMC–/– mice displayed significantly reduced responses to ATII, both in vivo and ex vivo. HF IP3R1VSMC–/– mice developed significantly less afterload compared with HF IP3R1fl/fl mice and exhibited significantly attenuated progression toward decompensated HF and reduced interstitial fibrosis. Ca2+-dependent phosphorylation of the MLC by MLCK activated VSMC contraction. MLC phosphorylation was markedly increased in VSMCs from patients with HF and HF mice but reduced in VSMCs from HF IP3R1VSMC–/– mice and HF WT mice treated with ML-7. Taken together, our data indicate that VSMC IP3R1 is a major effector of increased vascular tone, which contributes to increased cardiac afterload and decompensation in HF. |
| first_indexed | 2024-04-12T10:21:05Z |
| format | Article |
| id | doaj.art-0a9867fb920b4c0a8a3138de89ee96cd |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-04-12T10:21:05Z |
| publishDate | 2022-02-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-0a9867fb920b4c0a8a3138de89ee96cd2022-12-22T03:37:05ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-02-011324IP3 receptor orchestrates maladaptive vascular responses in heart failureHaikel DridiGaetano SantulliJessica GambardellaStanislovas S. JankauskasQi YuanJingyi YangSteven ReikenXujun WangAnetta WronskaXiaoping LiuAlain LacampagneAndrew R. MarksPatients with heart failure (HF) have augmented vascular tone, which increases cardiac workload, impairing ventricular output and promoting further myocardial dysfunction. The molecular mechanisms underlying the maladaptive vascular responses observed in HF are not fully understood. Vascular smooth muscle cells (VSMCs) control vasoconstriction via a Ca2+-dependent process, in which the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) on the sarcoplasmic reticulum (SR) plays a major role. To dissect the mechanistic contribution of intracellular Ca2+ release to the increased vascular tone observed in HF, we analyzed the remodeling of IP3R1 in aortic tissues from patients with HF and from controls. VSMC IP3R1 channels from patients with HF and HF mice were hyperphosphorylated by both serine and tyrosine kinases. VSMCs isolated from IP3R1VSMC–/– mice exhibited blunted Ca2+ responses to angiotensin II (ATII) and norepinephrine compared with control VSMCs. IP3R1VSMC–/– mice displayed significantly reduced responses to ATII, both in vivo and ex vivo. HF IP3R1VSMC–/– mice developed significantly less afterload compared with HF IP3R1fl/fl mice and exhibited significantly attenuated progression toward decompensated HF and reduced interstitial fibrosis. Ca2+-dependent phosphorylation of the MLC by MLCK activated VSMC contraction. MLC phosphorylation was markedly increased in VSMCs from patients with HF and HF mice but reduced in VSMCs from HF IP3R1VSMC–/– mice and HF WT mice treated with ML-7. Taken together, our data indicate that VSMC IP3R1 is a major effector of increased vascular tone, which contributes to increased cardiac afterload and decompensation in HF.https://doi.org/10.1172/JCI152859CardiologyCell biology |
| spellingShingle | Haikel Dridi Gaetano Santulli Jessica Gambardella Stanislovas S. Jankauskas Qi Yuan Jingyi Yang Steven Reiken Xujun Wang Anetta Wronska Xiaoping Liu Alain Lacampagne Andrew R. Marks IP3 receptor orchestrates maladaptive vascular responses in heart failure The Journal of Clinical Investigation Cardiology Cell biology |
| title | IP3 receptor orchestrates maladaptive vascular responses in heart failure |
| title_full | IP3 receptor orchestrates maladaptive vascular responses in heart failure |
| title_fullStr | IP3 receptor orchestrates maladaptive vascular responses in heart failure |
| title_full_unstemmed | IP3 receptor orchestrates maladaptive vascular responses in heart failure |
| title_short | IP3 receptor orchestrates maladaptive vascular responses in heart failure |
| title_sort | ip3 receptor orchestrates maladaptive vascular responses in heart failure |
| topic | Cardiology Cell biology |
| url | https://doi.org/10.1172/JCI152859 |
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