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751. From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on “New frontiers in cardiovascular research”

Author

Cabrera-Fuentes H., Aragones J., Bernhagen J., Boening A., Boisvert W., Bøtker H., Bulluck H., Cook S., Di Lisa F., Engel F., Engelmann B., Ferrazzi F., Ferdinandy P., Fong A., Fleming I., Gnaiger E., Hernández-Reséndiz S., Kalkhoran S., Kim M., Lecour S., Liehn E., Marber M., Mayr M., Miura T., Ong S., Peter K., Sedding D., Singh M., Suleiman M., Schnittler H., Schulz R., Shim W., Tello D., Vogel C., Walker M., Li Q., Yellon D., Hausenloy D., Preissner K., Cabrera-Fuentes H., Aragones J., Bernhagen J., Boening A., Boisvert W., Bøtker H., Bulluck H., Cook S., Di Lisa F., Engel F., Engelmann B., Ferrazzi F., Ferdinandy P., Fong A., Fleming I., Gnaiger E., Hernández-Reséndiz S., Kalkhoran S., Kim M., Lecour S., Liehn E., Marber M., Mayr M., Miura T., Ong S., Peter K., Sedding D., Singh M., Suleiman M., Schnittler H., Schulz R., Shim W., Tello D., Vogel C., Walker M., Li Q., Yellon D., Hausenloy D., and Preissner K.

Abstract

© 2016, The Author(s).In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients’ cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia–reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients’ outcome.

752. From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on “New frontiers in cardiovascular research”

Author

Cabrera-Fuentes H., Aragones J., Bernhagen J., Boening A., Boisvert W., Bøtker H., Bulluck H., Cook S., Di Lisa F., Engel F., Engelmann B., Ferrazzi F., Ferdinandy P., Fong A., Fleming I., Gnaiger E., Hernández-Reséndiz S., Kalkhoran S., Kim M., Lecour S., Liehn E., Marber M., Mayr M., Miura T., Ong S., Peter K., Sedding D., Singh M., Suleiman M., Schnittler H., Schulz R., Shim W., Tello D., Vogel C., Walker M., Li Q., Yellon D., Hausenloy D., Preissner K., Cabrera-Fuentes H., Aragones J., Bernhagen J., Boening A., Boisvert W., Bøtker H., Bulluck H., Cook S., Di Lisa F., Engel F., Engelmann B., Ferrazzi F., Ferdinandy P., Fong A., Fleming I., Gnaiger E., Hernández-Reséndiz S., Kalkhoran S., Kim M., Lecour S., Liehn E., Marber M., Mayr M., Miura T., Ong S., Peter K., Sedding D., Singh M., Suleiman M., Schnittler H., Schulz R., Shim W., Tello D., Vogel C., Walker M., Li Q., Yellon D., Hausenloy D., and Preissner K.

Abstract

© 2016, The Author(s).In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients’ cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia–reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients’ outcome.

753. Vývoj materiálu na bázi hydrogelů kyseliny hyaluronové pro regeneraci myokardu

Author

Pekař, Miloslav, Kubala,, Lukáš, Prokš,, Vladimír, Pekař, Miloslav, Kubala,, Lukáš, and Prokš,, Vladimír

Abstract

Tato disertační práce je zaměřena na vývoj materiálů na bázi kyseliny hyaluronové (HA) využitelných v regenerativní medicíně, především pro léčbu srdeční tkáně po infarktu myokardu. Předmětem studia je oxidovaná forma HA (HA-Ox) a hydroxyfenyl derivát HA (HA-TA). HA-Ox lze zesítit pomocí bifunkčního alkoxyaminu POA a HA-TA podstupuje ve vodném prostředí v přítomnosti peroxidu vodíku enzymatickou reakci katalyzovanou křenovou peroxidázou, vedoucí k tvorbě gelu. Cílem bylo studium chemických a fyzikálních vlastností, kinetiky gelace a podmínek síťovací reakce vyvíjených materiálů. U hydrogelů byly charakterizovány mechanické a viskoelastické vlastnosti, degradabilita či stabilita v simulovaných tělních tekutinách. Tyto hydrogely slouží jako scaffoldy pro vybraný typ buněk. Pro podporu buněčné adheze a viability byla do struktury hydroxyfenyl derivátu HA navázána RGD sekvence. Tento finální materiál byl také kompatibilní s vybranými aplikačními zařízeními. Jeho viskozita a výtlačná síla byla dostatečné nízká, aby umožnila aplikaci pomocí katetru s velmi malým vnitřním průměrem. Také byla zajištěna aplikovatelnost materiálu přes přívodní hadičku do nosné kapsy druhého zařízení SPREADS s dobrou homogenitou, buněčnou distribucí a viabilitou. V neposlední řadě byl materiál aplikován pomocí těchto zařízení in vivo během preklinické studie., The thesis is focused on material development based on hyaluronic acid usable in regenerative medicine, especially for heart tissue regeneration after myocardial infarction. The object of the study is the oxidized form of hyaluronic acid (HA-Ox) and hydroxyphenyl derivative of HA (HA-TA). HA-Ox can be crosslinked with a bifunctional alkoxyamine POA and HA-TA undergoes an enzymatic reaction in the presence of hydrogen peroxide catalysed by horseradish peroxidase leading to gel formation. To describe the materials, chemical and physical properties, gelation kinetics and conditions of crosslinking reactions were studied. Hydrogels were characterized by mechanical and viscoelastic properties, degradability or stability in simulated body fluids. These hydrogels serve as scaffolds for the selected cell type. To promote cell adhesion and viability, an RGD sequence has been bonded to the structure of HA-TA. This resulting material is also compatible with selected applicators. Its viscosity and extrusion force are low enough to allow application with a catheter with a very small internal diameter. The applicability of the material through the supply tube to the hydrogel reservoir of the second SPREADS device showed good homogeneity, cell distribution and viability. Finally, the material was applied in vivo using these devices during a preclinical study.

754. Vývoj materiálu na bázi hydrogelů kyseliny hyaluronové pro regeneraci myokardu

Author

Pekař, Miloslav, Kubala,, Lukáš, Prokš,, Vladimír, Pekař, Miloslav, Kubala,, Lukáš, and Prokš,, Vladimír

Abstract

Tato disertační práce je zaměřena na vývoj materiálů na bázi kyseliny hyaluronové (HA) využitelných v regenerativní medicíně, především pro léčbu srdeční tkáně po infarktu myokardu. Předmětem studia je oxidovaná forma HA (HA-Ox) a hydroxyfenyl derivát HA (HA-TA). HA-Ox lze zesítit pomocí bifunkčního alkoxyaminu POA a HA-TA podstupuje ve vodném prostředí v přítomnosti peroxidu vodíku enzymatickou reakci katalyzovanou křenovou peroxidázou, vedoucí k tvorbě gelu. Cílem bylo studium chemických a fyzikálních vlastností, kinetiky gelace a podmínek síťovací reakce vyvíjených materiálů. U hydrogelů byly charakterizovány mechanické a viskoelastické vlastnosti, degradabilita či stabilita v simulovaných tělních tekutinách. Tyto hydrogely slouží jako scaffoldy pro vybraný typ buněk. Pro podporu buněčné adheze a viability byla do struktury hydroxyfenyl derivátu HA navázána RGD sekvence. Tento finální materiál byl také kompatibilní s vybranými aplikačními zařízeními. Jeho viskozita a výtlačná síla byla dostatečné nízká, aby umožnila aplikaci pomocí katetru s velmi malým vnitřním průměrem. Také byla zajištěna aplikovatelnost materiálu přes přívodní hadičku do nosné kapsy druhého zařízení SPREADS s dobrou homogenitou, buněčnou distribucí a viabilitou. V neposlední řadě byl materiál aplikován pomocí těchto zařízení in vivo během preklinické studie., The thesis is focused on material development based on hyaluronic acid usable in regenerative medicine, especially for heart tissue regeneration after myocardial infarction. The object of the study is the oxidized form of hyaluronic acid (HA-Ox) and hydroxyphenyl derivative of HA (HA-TA). HA-Ox can be crosslinked with a bifunctional alkoxyamine POA and HA-TA undergoes an enzymatic reaction in the presence of hydrogen peroxide catalysed by horseradish peroxidase leading to gel formation. To describe the materials, chemical and physical properties, gelation kinetics and conditions of crosslinking reactions were studied. Hydrogels were characterized by mechanical and viscoelastic properties, degradability or stability in simulated body fluids. These hydrogels serve as scaffolds for the selected cell type. To promote cell adhesion and viability, an RGD sequence has been bonded to the structure of HA-TA. This resulting material is also compatible with selected applicators. Its viscosity and extrusion force are low enough to allow application with a catheter with a very small internal diameter. The applicability of the material through the supply tube to the hydrogel reservoir of the second SPREADS device showed good homogeneity, cell distribution and viability. Finally, the material was applied in vivo using these devices during a preclinical study.

755. Vývoj materiálu na bázi hydrogelů kyseliny hyaluronové pro regeneraci myokardu

Author

Pekař, Miloslav, Kubala,, Lukáš, Prokš,, Vladimír, Pekař, Miloslav, Kubala,, Lukáš, and Prokš,, Vladimír

Abstract

Tato disertační práce je zaměřena na vývoj materiálů na bázi kyseliny hyaluronové (HA) využitelných v regenerativní medicíně, především pro léčbu srdeční tkáně po infarktu myokardu. Předmětem studia je oxidovaná forma HA (HA-Ox) a hydroxyfenyl derivát HA (HA-TA). HA-Ox lze zesítit pomocí bifunkčního alkoxyaminu POA a HA-TA podstupuje ve vodném prostředí v přítomnosti peroxidu vodíku enzymatickou reakci katalyzovanou křenovou peroxidázou, vedoucí k tvorbě gelu. Cílem bylo studium chemických a fyzikálních vlastností, kinetiky gelace a podmínek síťovací reakce vyvíjených materiálů. U hydrogelů byly charakterizovány mechanické a viskoelastické vlastnosti, degradabilita či stabilita v simulovaných tělních tekutinách. Tyto hydrogely slouží jako scaffoldy pro vybraný typ buněk. Pro podporu buněčné adheze a viability byla do struktury hydroxyfenyl derivátu HA navázána RGD sekvence. Tento finální materiál byl také kompatibilní s vybranými aplikačními zařízeními. Jeho viskozita a výtlačná síla byla dostatečné nízká, aby umožnila aplikaci pomocí katetru s velmi malým vnitřním průměrem. Také byla zajištěna aplikovatelnost materiálu přes přívodní hadičku do nosné kapsy druhého zařízení SPREADS s dobrou homogenitou, buněčnou distribucí a viabilitou. V neposlední řadě byl materiál aplikován pomocí těchto zařízení in vivo během preklinické studie., The thesis is focused on material development based on hyaluronic acid usable in regenerative medicine, especially for heart tissue regeneration after myocardial infarction. The object of the study is the oxidized form of hyaluronic acid (HA-Ox) and hydroxyphenyl derivative of HA (HA-TA). HA-Ox can be crosslinked with a bifunctional alkoxyamine POA and HA-TA undergoes an enzymatic reaction in the presence of hydrogen peroxide catalysed by horseradish peroxidase leading to gel formation. To describe the materials, chemical and physical properties, gelation kinetics and conditions of crosslinking reactions were studied. Hydrogels were characterized by mechanical and viscoelastic properties, degradability or stability in simulated body fluids. These hydrogels serve as scaffolds for the selected cell type. To promote cell adhesion and viability, an RGD sequence has been bonded to the structure of HA-TA. This resulting material is also compatible with selected applicators. Its viscosity and extrusion force are low enough to allow application with a catheter with a very small internal diameter. The applicability of the material through the supply tube to the hydrogel reservoir of the second SPREADS device showed good homogeneity, cell distribution and viability. Finally, the material was applied in vivo using these devices during a preclinical study.

756. Harnessing the early post-injury inflammatory responses for cardiac regeneration

Author

Bill Cheng, Hung-Chih Chen, I. W. Chou, Patrick C.H. Hsieh, and Tony W. H. Tang

Subjects
0301 basic medicine, Cardiac function curve, Chemokine, Macrophage, Neutrophils, Cardiac fibrosis, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Myocardial Infarction, Infarction, Inflammation, Review, Monocytes, 03 medical and health sciences, Animals, Humans, Regeneration, Medicine, Pharmacology (medical), Myocardial infarction, Molecular Biology, Biochemistry, medical, Innate immune system, biology, business.industry, Macrophages, Myocardium, Biochemistry (medical), General Medicine, Cell Biology, medicine.disease, Immunity, Innate, 030104 developmental biology, Cell Transdifferentiation, Immunology, biology.protein, cardiovascular system, Chemokines, medicine.symptom, business, Heart regeneration
Abstract

Cardiac inflammation is considered by many as the main driving force in prolonging the pathological condition in the heart after myocardial infarction. Immediately after cardiac ischemic injury, neutrophils are the first innate immune cells recruited to the ischemic myocardium within the first 24 h. Once they have infiltrated the injured myocardium, neutrophils would then secret proteases that promote cardiac remodeling and chemokines that enhance the recruitment of monocytes from the spleen, in which the recruitment peaks at 72 h after myocardial infarction. Monocytes would transdifferentiate into macrophages after transmigrating into the infarct area. Both neutrophils and monocytes-derived macrophages are known to release proteases and cytokines that are detrimental to the surviving cardiomyocytes. Paradoxically, these inflammatory cells also play critical roles in repairing the injured myocardium. Depletion of either neutrophils or monocytes do not improve overall cardiac function after myocardial infarction. Instead, the left ventricular function is further impaired and cardiac fibrosis persists. Moreover, the inflammatory microenvironment created by the infiltrated neutrophils and monocytes-derived macrophages is essential for the recruitment of cardiac progenitor cells. Recent studies also suggest that treatment with anti-inflammatory drugs may cause cardiac dysfunction after injury. Indeed, clinical studies have shown that traditional ant-inflammatory strategies are ineffective to improve cardiac function after infarction. Thus, the focus should be on how to harness these inflammatory events to either improve the efficacy of the delivered drugs or to favor the recruitment of cardiac progenitor cells.

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757. Common Regulatory Pathways Mediate Activity of MicroRNAs Inducing Cardiomyocyte Proliferation

Author

Mauro Giacca, Lorena Zentilin, Ryan John Cubero, Areejit Samal, Ellen Dirkx, Giulia Prosdocimo, Maria Ines Gutierrez, Consuelo Torrini, Danilo Licastro, Serena Zacchigna, Hashim Ali, Chiara Collesi, Miguel Mano, Michele Vendruscolo, Luca Braga, Matteo Marsili, Cardiologie, RS: CARIM - R2.07 - Gene regulation, RS: Carim - H05 Gene regulation, Torrini, Consuelo, Cubero, Ryan John, Dirkx, Ellen, Braga, Luca, Ali, Hashim, Prosdocimo, Giulia, Gutierrez, Maria Ine, Collesi, Chiara, Licastro, Danilo, Zentilin, Lorena, Mano, Miguel, Zacchigna, Serena, Vendruscolo, Michele, Marsili, Matteo, Samal, Areejit, and Giacca, Mauro

Subjects
0301 basic medicine, Male, HIPPO, cardiomyocyte, Growth, Mirnas, 0302 clinical medicine, Hippo, Myocytes, Cardiac, Phosphorylation, Cytoskeleton, lcsh:QH301-705.5, YAP1, biology, microRNA, Chemistry, COFILIN, cytoskeleton, Cofilin, 3. Good health, Ubiquitin ligase, Cell biology, Actin Cytoskeleton, Female, cell cycle, YAP, Heart regeneration, Cofilin 2, Yap1, macromolecular substances, Filamentous actin, General Biochemistry, Genetics and Molecular Biology, Article, Cofilin2, regeneration, ACTIN, 03 medical and health sciences, Animals, Cell Proliferation, Hippo signaling pathway, YAP-Signaling Proteins, CLUSTER, Actin cytoskeleton, Rats, MicroRNAs, 030104 developmental biology, Animals, Newborn, lcsh:Biology (General), biology.protein, Apoptosis Regulatory Proteins, 030217 neurology & neurosurgery, Nuclear localization sequence, Biomarkers
Abstract

Summary Loss of functional cardiomyocytes is a major determinant of heart failure after myocardial infarction. Previous high throughput screening studies have identified a few microRNAs (miRNAs) that can induce cardiomyocyte proliferation and stimulate cardiac regeneration in mice. Here, we show that all of the most effective of these miRNAs activate nuclear localization of the master transcriptional cofactor Yes-associated protein (YAP) and induce expression of YAP-responsive genes. In particular, miR-199a-3p directly targets two mRNAs coding for proteins impinging on the Hippo pathway, the upstream YAP inhibitory kinase TAOK1, and the E3 ubiquitin ligase β-TrCP, which leads to YAP degradation. Several of the pro-proliferative miRNAs (including miR-199a-3p) also inhibit filamentous actin depolymerization by targeting Cofilin2, a process that by itself activates YAP nuclear translocation. Thus, activation of YAP and modulation of the actin cytoskeleton are major components of the pro-proliferative action of miR-199a-3p and other miRNAs that induce cardiomyocyte proliferation., Graphical Abstract, Highlights • A few microRNAs can stimulate cardiac myocyte proliferation • The most effective of these microRNAs activate YAP • Several pro-proliferative microRNAs also inhibit actin depolymerization • miR-199a-3p directly targets TAOK1, b-TrCP, and Cofilin2 to achieve its effects, Torrini et al. report that several microRNAs that induce cardiomyocyte proliferation act by stimulating activation of the transcriptional cofactor YAP, a master regulator of cell proliferation. Several microRNAs also act on the cardiomyocyte cytoskeleton by promoting actin polymerization. These microRNAs can be considered as potential treatments for cardiac regeneration.

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