Region- and Cell-type-Resolved Multiomic Atlas of the Heart.

Abstract

The heart is a vital muscular organ in vertebrate animals, responsible for maintaining blood circulation through rhythmic contraction. Although previous studies have investigated the heart proteome, the full hierarchical molecular network at cell-type- and region-resolved level, illustrating the specialized roles and crosstalk among different cell-types and regions, remains unclear. Here, we presented an atlas of cell-type-resolved proteome for mouse heart and region-resolved proteome for both mouse and human hearts. In-depth proteomic analysis identified 11,794 proteins across four cell-types and 11,995 proteins across six regions of the mouse heart. To further illustrate protein expression patterns in both physiological and pathological conditions, we conducted proteomic analysis on human heart samples from four regions with dilated cardiomyopathy (DCM). We quantified 8201 proteins in DCM tissue and 8316 proteins in adjacent unaffected myocardium tissue across the four human heart regions. Notably, we found that the retinoic acid synthesis pathway was significantly enriched in the DCM-affected left ventricle, and functional experiments demonstrated that all-trans retinoic acid efficiently rescued Ang II-induced myocardial hypertrophy and transverse aorta constriction-induced heart failure. In conclusion, our datasets uncovered the functional features of different cell-types and their synergistic cooperation centered by cell-type-specific transcription factors (TFs) in different regions, while these TF-TG (target gene) axes were significantly altered in DCM. Additionally, all-trans retinoic acid was demonstrated to be an efficient treatment for heart failure. This work presented a panoramic heart proteome map, offering a valuable resource for future cardiovascular research.