Role of platelet-derived calpain in diabetes-associated vascular diseases.
Final Report Abstract
The initial goal of this project was to understand the role of extracellular/platelet-derived calpains in diabetes-associated vascular complications. The first funding period focused on three aims: 1. the identification of new calpain substrates on the surface of endothelial cells, 2. the characterization of the role of extracellular calpain in vascular reactivity and inflammation and 3. the investigation of the role of extracellular calpain in angiogenesis and vascular repair. We could successfully clarifiy aims 1 and 2 but did not manage to assess aim 3. We could show that calpain 1 carried by platelet-derived microparticles (PMPs) is largely involved in the alteration of vascular integrity and the increased vascular inflammation in diabetes by targeting the glycocalyx and the PAR-1 receptor on the endothelial cells. PAR-1 cleavage initiated intracellular signaling cascade leading to vascular inflammation in diabetes. Given that diabetes-associated vascular complications involve a complex interplay between the vascular wall and circulating cells, the aim of the second funding period was to analyze the effect of extracellular calpain 1 on circulating cells such as monocytes and neutrophils. Due to the difficulty collecting enough samples from diabetic patients, samples from women with polycystic ovary syndrome (PCOS) were investigated during the second funding period. Although deviating from the initial plan, these studies led to interesting new findings. We could show that in addition to expressing active calpain, platelets from PCOS patients demonstrate enhanced arginase levels and activity. We demonstrated that increased levels of arginasebearing PMPs contribute to the alteration of the arginine metabolism in patients with PCOS. Further investigation of platelets from PCOS led us to the finding that platelets are a source of collagen I and that levels were significantly enhanced in PCOS. In addition, we have identified Cyclin Y to be expressed in platelets and we have characterized its role in platelets. In summary, this project resulted in several important findings that clarify the molecular mechanisms of vascular complications associated to diabetes. We have identified new calpain substrates on the vascular wall as well as new proteins expressed by platelets.
Publications
- Platelets as potential link between diabetes and Alzheimer`s disease. Curr Alzheimer Res 2014. 11(9):862-8
Randriamboavonjy V, Sopova K, Stellos K, Laske C
(See online at https://doi.org/10.2174/156720501109141013115258) - Dicer cleavage by calpain determines platelet microRNA levels and function in diabetes. Circ Res. 2015. 117(2):157-65
Elgheznawy A, Shi L, Hu J, Wittig I, Laban H, Pircher J, Mann A, Provost P, Randriamboavonjy V, Fleming I
(See online at https://doi.org/10.1161/CIRCRESAHA.117.305784) - Increased cerebrospinal fluid calpain activity and microparticle levels in Alzheimer´s disease. Alzheimers Dement 2015. 11(5):465-474
Laske C, Stellos K, Kempter I, Stransky E, Maetzler W, Fleming I, Randriamboavonjy V
(See online at https://doi.org/10.1016/j.jalz.2014.06.003) - Metformin reduces hyper-reactivity of platelets from patients with polycystic ovary syndrome by improving mitochondrial integrity. Thromb Haemost. 2015. 114(3):569-78
Randriamboavonjy V, Mann AW, Elgheznawy A, Popp R, Rogowski P, Dornauf I, Dröse S, Fleming I
(See online at https://doi.org/10.1160/TH14-09-0797) - Calpain 1 cleaves and inactivates prostacyclin synthase in mesenteric arteries from diabetic mice. Basic Res Cardiol. 2017 112(1):10
Randriamboavonjy V, Kyselova A, Elgheznawy A, Zukunft S, Wittig I, Fleming I
(See online at https://doi.org/10.1007/s00395-016-0596-8) - Platelet activation and communication with the vascular wall. Clin Sci. 2018. 132(17):1875-1888
Randriamboavonjy V, Fleming I
(See online at https://doi.org/10.1042/CS20180580) - Redox-regulation of calpains: consequences on vascular function. Antioxid Redox Signal. 2018
Randriamboavonjy V, Kyselova A, Fleming I
(See online at https://doi.org/10.1089/ars.2018.7607) - Association between arginase-containing platelet-derived microparticles and altered plasma arginine metabolism in polycystic ovary syndrome. Metabolism. 2019; 90:16-19
Kyselova A, Hinrichsmeyer H, Zukunft S, Mann AW, Dornauf I, Fleming I, Randriamboavonjy V
(See online at https://doi.org/10.1016/j.metabol.2018.10.008) - Regulation of calpain 2 expression by miR-223 and miR-145. Biochim Biophys Acta Gene Regul Mech. 2019 Oct 18:194438
Siuda D, Randriamboavonjy V, Fleming I
(See online at https://doi.org/10.1016/j.bbagrm.2019.194438) - Human platelets are a source of collagen I. Haematologica 2020; Jun 18: haematol.2020.255612
Kyselova A, Zukunft S, Puppe D, Wittig I, Mann WA, Dornauf I, Fleming I, Randriamboavonjy V
(See online at https://doi.org/10.3324/haematol.2020.255612)
