Chondroitin sulfate proteoglycan 4,6 sulfation regulates sympathetic nerve regeneration after myocardial infarction
Sympathetic denervation of the heart following ischemia/reperfusion induced myocardial infarction (MI) is sustained by chondroitin sulfate proteoglycans (CSPGs) in the cardiac scar. Denervation predicts risk of sudden cardiac death in humans. Blocking CSPG signaling restores sympathetic axon outgrow...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/78387 |
| _version_ | 1818018412873383936 |
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| author | Matthew R Blake Diana C Parrish Melanie A Staffenson Shanice Sueda William R Woodward Beth A Habecker |
| author_facet | Matthew R Blake Diana C Parrish Melanie A Staffenson Shanice Sueda William R Woodward Beth A Habecker |
| author_sort | Matthew R Blake |
| collection | DOAJ |
| description | Sympathetic denervation of the heart following ischemia/reperfusion induced myocardial infarction (MI) is sustained by chondroitin sulfate proteoglycans (CSPGs) in the cardiac scar. Denervation predicts risk of sudden cardiac death in humans. Blocking CSPG signaling restores sympathetic axon outgrowth into the cardiac scar, decreasing arrhythmia susceptibility. Axon growth inhibition by CSPGs can depend on the sulfation status of the glycosaminoglycan (CS-GAG) side chains. Tandem sulfation of CS-GAGs at the 4th (4S) and 6th (6S) positions of n-acetyl-galactosamine inhibits outgrowth in several types of central neurons, but we don’t know if sulfation is similarly critical during peripheral nerve regeneration. We asked if CSPG sulfation prevented sympathetic axon outgrowth after MI. Reducing 4S with the 4-sulfatase enzyme Arylsulfatase-B (ARSB) enhanced outgrowth of dissociated rat sympathetic neurons over CSPGs. Likewise, reducing 4S with ARSB restored axon outgrowth from mouse sympathetic ganglia co-cultured with cardiac scar tissue. We quantified enzymes responsible for adding and removing sulfation, and found that CHST15 (4S dependent 6-sulfotransferase) was upregulated, and ARSB was downregulated after MI. This suggests a mechanism for production and maintenance of sulfated CSPGs in the cardiac scar. We decreased 4S,6S CS-GAGs in vivo by transient siRNA knockdown of Chst15 after MI, and found that reducing 4S,6S restored tyrosine hydroxylase (TH) positive sympathetic nerve fibers in the cardiac scar. Reinnervation reduced isoproterenol induced arrhythmias. Our results suggest that modulating CSPG-sulfation after MI may be a therapeutic target to promote sympathetic nerve regeneration in the cardiac scar and reduce post-MI cardiac arrhythmias. |
| first_indexed | 2024-04-14T07:39:55Z |
| format | Article |
| id | doaj.art-d6ecbe0551b6479984c4b2b438b21fc2 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:39:55Z |
| publishDate | 2022-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d6ecbe0551b6479984c4b2b438b21fc22022-12-22T02:05:33ZengeLife Sciences Publications LtdeLife2050-084X2022-05-011110.7554/eLife.78387Chondroitin sulfate proteoglycan 4,6 sulfation regulates sympathetic nerve regeneration after myocardial infarctionMatthew R Blake0https://orcid.org/0000-0003-0584-7684Diana C Parrish1Melanie A Staffenson2Shanice Sueda3William R Woodward4Beth A Habecker5https://orcid.org/0000-0002-4658-8730Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, United StatesDepartment of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, United StatesDepartment of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, United StatesPortland State University EXITO Scholars Program, Portland State University, Portland, United StatesDepartment of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, United StatesDepartment of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, United StatesSympathetic denervation of the heart following ischemia/reperfusion induced myocardial infarction (MI) is sustained by chondroitin sulfate proteoglycans (CSPGs) in the cardiac scar. Denervation predicts risk of sudden cardiac death in humans. Blocking CSPG signaling restores sympathetic axon outgrowth into the cardiac scar, decreasing arrhythmia susceptibility. Axon growth inhibition by CSPGs can depend on the sulfation status of the glycosaminoglycan (CS-GAG) side chains. Tandem sulfation of CS-GAGs at the 4th (4S) and 6th (6S) positions of n-acetyl-galactosamine inhibits outgrowth in several types of central neurons, but we don’t know if sulfation is similarly critical during peripheral nerve regeneration. We asked if CSPG sulfation prevented sympathetic axon outgrowth after MI. Reducing 4S with the 4-sulfatase enzyme Arylsulfatase-B (ARSB) enhanced outgrowth of dissociated rat sympathetic neurons over CSPGs. Likewise, reducing 4S with ARSB restored axon outgrowth from mouse sympathetic ganglia co-cultured with cardiac scar tissue. We quantified enzymes responsible for adding and removing sulfation, and found that CHST15 (4S dependent 6-sulfotransferase) was upregulated, and ARSB was downregulated after MI. This suggests a mechanism for production and maintenance of sulfated CSPGs in the cardiac scar. We decreased 4S,6S CS-GAGs in vivo by transient siRNA knockdown of Chst15 after MI, and found that reducing 4S,6S restored tyrosine hydroxylase (TH) positive sympathetic nerve fibers in the cardiac scar. Reinnervation reduced isoproterenol induced arrhythmias. Our results suggest that modulating CSPG-sulfation after MI may be a therapeutic target to promote sympathetic nerve regeneration in the cardiac scar and reduce post-MI cardiac arrhythmias.https://elifesciences.org/articles/78387chondroitin sulfate proteoglycansympathetic nervesnerve regenerationmyocardial infarction |
| spellingShingle | Matthew R Blake Diana C Parrish Melanie A Staffenson Shanice Sueda William R Woodward Beth A Habecker Chondroitin sulfate proteoglycan 4,6 sulfation regulates sympathetic nerve regeneration after myocardial infarction eLife chondroitin sulfate proteoglycan sympathetic nerves nerve regeneration myocardial infarction |
| title | Chondroitin sulfate proteoglycan 4,6 sulfation regulates sympathetic nerve regeneration after myocardial infarction |
| title_full | Chondroitin sulfate proteoglycan 4,6 sulfation regulates sympathetic nerve regeneration after myocardial infarction |
| title_fullStr | Chondroitin sulfate proteoglycan 4,6 sulfation regulates sympathetic nerve regeneration after myocardial infarction |
| title_full_unstemmed | Chondroitin sulfate proteoglycan 4,6 sulfation regulates sympathetic nerve regeneration after myocardial infarction |
| title_short | Chondroitin sulfate proteoglycan 4,6 sulfation regulates sympathetic nerve regeneration after myocardial infarction |
| title_sort | chondroitin sulfate proteoglycan 4 6 sulfation regulates sympathetic nerve regeneration after myocardial infarction |
| topic | chondroitin sulfate proteoglycan sympathetic nerves nerve regeneration myocardial infarction |
| url | https://elifesciences.org/articles/78387 |
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