Several genetic defects, including a mutation in myosin heavy chain 11 (Myh11), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, despite the absence of major pathological phenotypic abnormalities prior to stimulation. In this study, we used a comprehensive, data-driven, unbiased, multi-omics approach to find underlying changes in transcription and metabolism that predispose the aorta to dissection in mice harboring the Myh11 K1256del mutation. Pathway analysis of transcriptomes showed that genes involved in membrane transport were downregulated in homozygous mutant (Myh11ΔK/ΔK) aortas. Furthermore, expanding the analysis with metabolomics showed that two mechanisms that raise the cytosolic Ca2+ concentration-multiple calcium channel expression and ADP-ribose synthesis-were attenuated in Myh11ΔK/ΔK aortas. We suggest that the impairment of the Ca2+ influx attenuates aortic contraction and that suboptimal contraction predisposes the aorta to dissection.
Keywords: calcium transport; familial thoracic aortic aneurysm and dissection; multi-omics.