Cells and gene expression programs in the adult human heart

Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and strategies to improve therapeutic opportunities require deeper understanding of the molecular processes of the normal heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavor. Here, using large-scale single cell and nuclei transcriptomic profiling together with state-of-the-art analytical techniques, we characterise the adult human heart cellular landscape covering six anatomical cardiac regions (left and right atria and ventricles, apex and interventricular septum). Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, revealing distinct subsets in the atria and ventricles indicative of diverse developmental origins and specialized properties. Further we define the complexity of the cardiac vascular network which includes clusters of arterial, capillary, venous, lymphatic endothelial cells and an atrial-enriched population. By comparing cardiac cells to skeletal muscle and kidney, we identify cardiac tissue resident macrophage subsets with transcriptional signatures indicative of both inflammatory and reparative phenotypes. Further, inference of cell-cell interactions highlight a macrophage-fibroblast-cardiomyocyte network that differs between atria and ventricles, and compared to skeletal muscle. We expect this reference human cardiac cell atlas to advance mechanistic studies of heart homeostasis and disease

The renin-angiotensin system: going beyond the classical paradigms

Thirty years ago a novel axis of the renin-angiotensin system (RAS) was unveiled by the discovery of angiotensin (Ang)-(1-7) generation in-vivo. Later angiotensin-converting enzyme 2 (ACE2) was shown to be the main mediator of this reaction and Mas was found to be the receptor for the heptapeptide. The functional analysis of this novel axis of the RAS which followed its discovery revealed numerous protective actions in particular for cardiovascular diseases. In parallel, similar protective actions were also described for one of the two receptors of Ang II, AT2R, in contrast to the other, AT1R, which mediates deleterious actions of this peptide e.g. in the setting of cardiovascular disease. Very recently, another branch of the RAS was discovered, based on Ang peptides in which the aminoterminal aspartate is replaced by alanine, the alatensins. Ala-Ang-(1-7) or alamandine was shown to interact with the Mas-related receptor (MrgD) and first functional data indicate that this peptide also exerts protective effects in the cardiovascular system. This review summarizes the presentations given at the International Union of Physiological Sciences Congress in Rio de Janeiro, 2017, during the symposium "The renin-angiotensin system: going beyond the classical paradigms", in which the signaling and the physiological actions of Ang-(1-7), ACE2, AT2R and the alatensins were reported (with a focus on non-CNS tissues) and the therapeutic opportunities based on these findings were discussed