Netrin-1: Focus on its role in cardiovascular physiology and atherosclerosis.

The netrins form a family of laminin-related proteins which were first described as modulators of cell migration and axonal guidance during fetal development. Netrin-1 is the most extensively studied member of this family and, since its discovery, non-neural roles have been associated with it. Together with its receptors, DCC/neogenin and UNC5, netrin-1 has been shown to be involved in the regulation of angiogenesis, organogenesis, cancer and inflammation. An NF-κB-dependent truncated isoform of netrin-1 has also been shown to be produced in endothelial and some types of cancer cells, which both accumulates in and affects the function of the nucleus. In atherosclerosis, conflicting roles for netrin-1 have been reported on plaque progression via its receptor UNC5b. Whereas endothelial-derived netrin-1 inhibits chemotaxis of leukocytes and reduces the migration of monocytes to the atherosclerotic plaque, netrin-1 expressed by macrophages within the plaque plays a pro-atherogenic role, promoting cell survival, recruiting smooth muscle cells and inhibiting foam cell egress to the lymphatic system. In contrast, there is evidence that netrin-1 promotes macrophage differentiation to an alternative activated phenotype and induces expression of IL-4 and IL-13, while downregulate expression of IL-6 and COX-2. Further work is needed to elucidate the precise roles of the two isoforms of netrin-1 in different cell types in the context of atherosclerosis, and its potential as a putative novel therapeutic target in this disease.

Cardiac optogenetics: using light to monitor cardiac physiology.

Our current understanding of cardiac excitation and its coupling to contraction is largely based on ex vivo studies utilising fluorescent organic dyes to assess cardiac action potentials and signal transduction. Recent advances in optogenetic sensors open exciting new possibilities for cardiac research and allow us to answer research questions that cannot be addressed using the classic organic dyes. Especially thrilling is the possibility to use optogenetic sensors to record parameters of cardiac excitation and contraction in vivo. In addition, optogenetics provide a high spatial resolution, as sensors can be coupled to motifs and targeted to specific cell types and subcellular domains of the heart. In this review, we will give a comprehensive overview of relevant optogenetic sensors, how they can be utilised in cardiac research and how they have been applied in cardiac research up to now.