Cardiac Remodeling Secondary to Chronic Volume Overload Is Attenuated by a Novel MMP9/2 Blocking Antibody
| Autor: | Gad Keren, Anna Aloshin, Irit Sagi, Einat Bigelman, Jeremy Ben-Shoshan, Zach Rozenbaum, Lena Cohen, Michal Entin-Meer, Inna Solomonov |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cardiac fibrosis Physiology medicine.medical_treatment Volume overload 030204 cardiovascular system & hematology Matrix metalloproteinase Pathology and Laboratory Medicine Biochemistry White Blood Cells 0302 clinical medicine Fibrosis Animal Cells Immune Physiology Medicine and Health Sciences Immune Response Energy-Producing Organelles Cardiomyocytes Vascular Fistula Innate Immune System Multidisciplinary Ventricular Remodeling Heart Animal Models Mitochondria Cytokine Experimental Organism Systems Matrix Metalloproteinase 9 Gelatinases Medicine Cytokines Matrix Metalloproteinase 2 Tumor necrosis factor alpha Cellular Structures and Organelles Cellular Types Anatomy Inflammation Mediators Research Article Dilatation Pathologic medicine.medical_specialty Science Immune Cells Heart Ventricles Immunology Muscle Tissue Mouse Models Bioenergetics Matrix Metalloproteinase Inhibitors Research and Analysis Methods Models Biological Mitochondrial Proteins 03 medical and health sciences Signs and Symptoms Model Organisms Diagnostic Medicine Internal medicine Blocking antibody medicine Animals Ventricular remodeling Antibodies Blocking Inflammation Muscle Cells Blood Cells business.industry Biology and Life Sciences Correction Cell Biology Molecular Development medicine.disease Mice Inbred C57BL 030104 developmental biology Endocrinology Biological Tissue Immune System Chronic Disease Cardiovascular Anatomy Animal Studies business Developmental Biology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 15, Iss 4, p e0231202 (2020) PLoS ONE, Vol 15, Iss 10, p e0241419 (2020) PLOS ONE |
| ISSN: | 1932-6203 |
| Popis: | Objective Monoclonal antibody derivatives are promising drugs for the treatment of various diseases due to their high matrix metalloproteinases (MMP) active site specificity. We studied the effects of a novel antibody, SDS3, which specifically recognizes the mature active site of MMP9/2 during ventricular remodeling progression in a mouse model of chronic volume overload (VO). Methods VO was induced by creating an aortocaval fistula (ACF) in 10- to 12-week-old C57BL male mice. The VO-induced mice were treated with either vehicle control (PBS) or with SDS3 twice weekly by intraperitoneal (ip) injection. The relative changes in cardiac parameters between baseline (day 1) and end-point (day 30), were evaluated by echocardiography. The effects of SDS3 treatment on cardiac fibrosis, cardiomyocyte volume, and cardiac inflammation were tested by cardiac staining with Masson's trichrome, wheat Germ Agglutinin (WGA), and CD45, respectively. Serum levels of TNFα and IL-6 with and without SDS3 treatment were tested by ELISA. Results SDS3 significantly reduced cardiac dilatation, left ventricular (LV) mass, and cardiomyocyte hypertrophy compared to the vehicle treated animals. The antibody also reduced the heart-to-body weight ratio of the ACF animals to values comparable to those of the controls. Interestingly, the SDS3 group underwent significant reduction of cardiac inflammation and pro-inflammatory cytokine production, indicating a regulatory role for MMP9/2 in tissue remodeling, possibly by tumor necrosis factor alpha (TNFα) activation. In addition, significant changes in the expression of proteins related to mitochondrial function were observed in ACF animals, these changes were reversed following treatment with SDS3. Conclusion The data suggest that MMP9/2 blockage with SDS3 attenuates myocardial remodeling associated with chronic VO by three potential pathways: downregulating the extracellular matrix proteolytic cleavage, reducing the cardiac inflammatory responses, and preserving the cardiac mitochondrial structure and function. |
| Databáze: | OpenAIRE |
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