HHS Public Access Author manuscript Author Manuscript
Stroke. Author manuscript; available in PMC 2017 June 01. Published in final edited form as: Stroke. 2016 June ; 47(6): e173. doi:10.1161/STROKEAHA.116.013283.
Response to Letter Regarding Article, "Matrix Metalloprotease 3 Exacerbates Hemorrhagic Transformation and Worsens Functional Outcomes in Hyperglycemic Stroke" Sherif Hafez, PhD1,2,3 and Adviye Ergul, MD, PhD1,2,3 1Charlie
Norwood VA Medical Center, Medical College of Georgia, Augusta University, Augusta,
Author Manuscript
GA 2Department
of Physiology, Medical College of Georgia, Augusta University, Augusta, GA
3Program
in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA
Keywords Stroke; Brain Ischemia; Intracranial Hemorrhage; Hyperglycemia; Matrix Metalloprotienase 3
Letter to the Editor Author Manuscript
Matrix metalloprotease 3 (MMP3) is a zinc endopeptidase that has the ability to digest and degrade the basal lamina and tight junction proteins causing increased blood brain barrier disruption.1 We showed that acute hyperglycemia increased MMP3 activity in the brain after stroke and this was associated with exacerbated cerebral hemorrhage and worse functional outcomes. Both pharmacological and molecular inhibition of MMP3 reduced the injury and improved the outcomes. It was previously shown that MMP3 plays a role in degrading tight junction proteins like occludin and claudin-5 in several neurological disorders.2, 3 However, this was not studied specifically in acute hyperglycemic stroke and we agree that this would be a good point for future studies.
Author Manuscript
We were also interested in showing the expression of MMP3 in the neurovascular unit, especially the vasculature, to correlate it to the bleeding occurring after stroke. It was previously shown that MMP3 released in response to neurodegeneration causes microglial activation and release of inflammatory cytokines like TNF alpha and IL-1B. In addition, activated microglia showed to express and release more MMP3 in response to neuroAddress for Correspondence, Adviye Ergul, MD, PhD, 1120 15th Street CA 2094, Department of Physiology, Augusta University, Augusta, GA 30912, Tel: 1-706-721-9103. Fax: 1-706-721-7299. ; Email: [email protected] Disclosures None Conflict of interest Sherif Hafez declares that he has no conflict of interest. Adviye Ergul declares that she has no conflict of interest.
Hafez and Ergul
Page 2
Author Manuscript
inflammation. This was extensively studied and reviewed by Kim et al.4 Accordingly, we think that microglial activation may be playing a crucial role in MMP3 induction and activation in hyperglycemic stroke and again, this may be another good point for future studies.
Acknowledgments Source of Funding Adviye Ergul is a Research Career Scientist at the Charlie Norwood Veterans Affairs Medical Center in Augusta, Georgia. This work was supported in part by VA Merit Award (BX000347), Veterans Affairs (VA) Research Career Scientists Award, and NIH (R01NS083559) to Adviye Ergul and American Heart Association Predoctoral Fellowship (13PRE17090026) to Sherif Hafez. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.
Author Manuscript
References 1. Jin R, Yang G, Li G. Molecular insights and therapeutic targets for blood-brain barrier disruption in ischemic stroke: Critical role of matrix metalloproteinases and tissue-type plasminogen activator. Neurobiol Dis. 2010; 38:376–385. [PubMed: 20302940] 2. Lee JY, Choi HY, Ahn HJ, Ju BG, Yune TY. Matrix metalloproteinase-3 promotes early blood-spinal cord barrier disruption and hemorrhage and impairs long-term neurological recovery after spinal cord injury. Am J Pathol. 2014; 184:2985–3000. [PubMed: 25325922] 3. Rosenberg GA, Yang Y. Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus. 2007; 22:E4. [PubMed: 17613235] 4. Kim EM, Hwang O. Role of matrix metalloproteinase-3 in neurodegeneration. J Neurochem. 2011; 116:22–32. [PubMed: 21044079]
Author Manuscript Author Manuscript Stroke. Author manuscript; available in PMC 2017 June 01.
Stroke. Author manuscript; available in PMC 2017 June 01. Published in final edited form as: Stroke. 2016 June ; 47(6): e173. doi:10.1161/STROKEAHA.116.013283.
Response to Letter Regarding Article, "Matrix Metalloprotease 3 Exacerbates Hemorrhagic Transformation and Worsens Functional Outcomes in Hyperglycemic Stroke" Sherif Hafez, PhD1,2,3 and Adviye Ergul, MD, PhD1,2,3 1Charlie
Norwood VA Medical Center, Medical College of Georgia, Augusta University, Augusta,
Author Manuscript
GA 2Department
of Physiology, Medical College of Georgia, Augusta University, Augusta, GA
3Program
in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA
Keywords Stroke; Brain Ischemia; Intracranial Hemorrhage; Hyperglycemia; Matrix Metalloprotienase 3
Letter to the Editor Author Manuscript
Matrix metalloprotease 3 (MMP3) is a zinc endopeptidase that has the ability to digest and degrade the basal lamina and tight junction proteins causing increased blood brain barrier disruption.1 We showed that acute hyperglycemia increased MMP3 activity in the brain after stroke and this was associated with exacerbated cerebral hemorrhage and worse functional outcomes. Both pharmacological and molecular inhibition of MMP3 reduced the injury and improved the outcomes. It was previously shown that MMP3 plays a role in degrading tight junction proteins like occludin and claudin-5 in several neurological disorders.2, 3 However, this was not studied specifically in acute hyperglycemic stroke and we agree that this would be a good point for future studies.
Author Manuscript
We were also interested in showing the expression of MMP3 in the neurovascular unit, especially the vasculature, to correlate it to the bleeding occurring after stroke. It was previously shown that MMP3 released in response to neurodegeneration causes microglial activation and release of inflammatory cytokines like TNF alpha and IL-1B. In addition, activated microglia showed to express and release more MMP3 in response to neuroAddress for Correspondence, Adviye Ergul, MD, PhD, 1120 15th Street CA 2094, Department of Physiology, Augusta University, Augusta, GA 30912, Tel: 1-706-721-9103. Fax: 1-706-721-7299. ; Email: [email protected] Disclosures None Conflict of interest Sherif Hafez declares that he has no conflict of interest. Adviye Ergul declares that she has no conflict of interest.
Hafez and Ergul
Page 2
Author Manuscript
inflammation. This was extensively studied and reviewed by Kim et al.4 Accordingly, we think that microglial activation may be playing a crucial role in MMP3 induction and activation in hyperglycemic stroke and again, this may be another good point for future studies.
Acknowledgments Source of Funding Adviye Ergul is a Research Career Scientist at the Charlie Norwood Veterans Affairs Medical Center in Augusta, Georgia. This work was supported in part by VA Merit Award (BX000347), Veterans Affairs (VA) Research Career Scientists Award, and NIH (R01NS083559) to Adviye Ergul and American Heart Association Predoctoral Fellowship (13PRE17090026) to Sherif Hafez. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.
Author Manuscript
References 1. Jin R, Yang G, Li G. Molecular insights and therapeutic targets for blood-brain barrier disruption in ischemic stroke: Critical role of matrix metalloproteinases and tissue-type plasminogen activator. Neurobiol Dis. 2010; 38:376–385. [PubMed: 20302940] 2. Lee JY, Choi HY, Ahn HJ, Ju BG, Yune TY. Matrix metalloproteinase-3 promotes early blood-spinal cord barrier disruption and hemorrhage and impairs long-term neurological recovery after spinal cord injury. Am J Pathol. 2014; 184:2985–3000. [PubMed: 25325922] 3. Rosenberg GA, Yang Y. Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus. 2007; 22:E4. [PubMed: 17613235] 4. Kim EM, Hwang O. Role of matrix metalloproteinase-3 in neurodegeneration. J Neurochem. 2011; 116:22–32. [PubMed: 21044079]
Author Manuscript Author Manuscript Stroke. Author manuscript; available in PMC 2017 June 01.
