Abstract P2041: Cytochrome P450 Reductase Prevents Cardiac Hypertrophy Through Crosstalk

The cytochrome P450 reductase (POR) transfers electrons and thus drives the function of all cytochrome P450-dependent enzymes (CYP450). In the vascular system, the CYP450-POR system has been linked to vascular epoxyeicosatrienoic acids (EET) production and endothelial function. The functional importance of the endothelial CYP450 system in the heart, however, is unclear and was studied here, using a tissue-specific deletion approach. RNAseq revealed that murine cardiac endothelial cells express POR as well as numerous CYPs, which have been linked to different functions: CYP2 family members produce EETs, whereas CYP4 family generated omega fatty acids. Endothelial-specific, tamoxifen-inducible POR knockout mice (ecPOR -/- ) show endothelial dysfunction and increased hypertensive response to angiotensin II infusion. ecPOR -/- mice also exhibited cardiac hypertrophy, an increase in cardiomyocyte area, a reduced ejection fraction and an increased left ventricle size during systole (echocardiography) as compared to control animals. RNAseq of isolated cardiac endothelial cells revealed that deletion of POR was associated with a significant decrease in genes linked to unfolded protein response (Xbp1, Hspa5) whereas genes related to cardiac development were upregulated (Sox4, Gata4). Furthermore, cardiac myocytes showed a reduced expression of genes linked to mitochondrial ATP production (Sdhaf4, Mtx1, Coq10b).Collectively, our data suggest that loss of endothelial POR promotes cardiac hypertrophy potentially by modulating paracrine signals of endothelial cells to cardiac myocytes.