Cyclic GMP-Dependent Regulation of Vascular Tone and Blood Pressure Involves Cysteine-Rich LIM-Only Protein 4 (CRP4)
| Autor: | Olga Schweigert, Julia Adler, Melanie Cruz Santos, Robert Lukowski, Tanja Zeller, Felicia Kleusberg, Amelie Knauer, Peter Ruth, Matthias Sausbier, Natalie Längst |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Vascular smooth muscle myofilament Vasodilator Agents Blood Pressure Muscle Smooth Vascular chemistry.chemical_compound Norepinephrine Soluble Guanylyl Cyclase Myosin Biology (General) Cyclic GMP Spectroscopy Cyclic GMP-Dependent Protein Kinase Type I Mice Knockout NO-GC PKG blood pressure regulation General Medicine LIM Domain Proteins cGKI Computer Science Applications Cell biology Chemistry Second messenger system Female Sodium nitroprusside medicine.drug Signal Transduction QH301-705.5 Myocytes Smooth Muscle Ca2+-sensitivity Models Biological Catalysis Article Nitric oxide Inorganic Chemistry Cinaciguat nitric oxide medicine Animals Calcium Signaling Physical and Theoretical Chemistry Protein kinase A vascular tone QD1-999 Molecular Biology Activator (genetics) Organic Chemistry VSMC CRP4 cGMP chemistry Blood Vessels |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 18 International Journal of Molecular Sciences, Vol 22, Iss 9925, p 9925 (2021) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22189925 |
| Popis: | The cysteine-rich LIM-only protein 4 (CRP4), a LIM-domain and zinc finger containing adapter protein, has been implicated as a downstream effector of the second messenger 3′,5′-cyclic guanosine monophosphate (cGMP) pathway in multiple cell types, including vascular smooth muscle cells (VSMCs). VSMCs and nitric oxide (NO)-induced cGMP signaling through cGMP-dependent protein kinase type I (cGKI) play fundamental roles in the physiological regulation of vascular tone and arterial blood pressure (BP). However, it remains unclear whether the vasorelaxant actions attributed to the NO/cGMP axis require CRP4. This study uses mice with a targeted deletion of the CRP4 gene (CRP4 KO) to elucidate whether cGMP-elevating agents, which are well known for their vasorelaxant properties, affect vessel tone, and thus, BP through CRP4. Cinaciguat, a NO- and heme-independent activator of the NO-sensitive (soluble) guanylyl cyclase (NO-GC) and NO-releasing agents, relaxed both CRP4-proficient and -deficient aortic ring segments pre-contracted with prostaglandin F2α. However, the magnitude of relaxation was slightly, but significantly, increased in vessels lacking CRP4. Accordingly, CRP4 KO mice presented with hypotonia at baseline, as well as a greater drop in systolic BP in response to the acute administration of cinaciguat, sodium nitroprusside, and carbachol. Mechanistically, loss of CRP4 in VSMCs reduced the Ca2+-sensitivity of the contractile apparatus, possibly involving regulatory proteins, such as myosin phosphatase targeting subunit 1 (MYPT1) and the regulatory light chain of myosin (RLC). In conclusion, the present findings confirm that the adapter protein CRP4 interacts with the NO-GC/cGMP/cGKI pathway in the vasculature. CRP4 seems to be part of a negative feedback loop that eventually fine-tunes the NO-GC/cGMP axis in VSMCs to increase myofilament Ca2+ desensitization and thereby the maximal vasorelaxant effects attained by (selected) cGMP-elevating agents. |
| Databáze: | OpenAIRE |
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