PYROCALM

Individuals with metabolic syndrome (MetS), and particularly those with type 2 diabetes, and/or metabolic dysfunction-associated steatohepatitis or MASH, are particularly prone to develop cardiovascular (CV) calcifications and to die due to CV events. The mechanisms leading to vascular calcification and its impact on CV mortality are poorly understood. We recently observed that in patients with MASH, progression of liver fibrosis is associated with reduced release in the blood of inorganic pyrophosphate (PPi), a necessary ectopic calcification inhibitor, and increased CV calcium deposition. Moreover, we also observed that in atherosclerotic mice with MetS, the enzyme know to stimulate bone mineralization by its ability to hydrolyze PPi, tissue-nonspecific alkaline phosphatase (TNAP), is expressed in the liver in association with fibrosis, and is responsible for aorta calcification. In this context, the objectives of the PYROCALM project are 1) to uncover the mechanism of action of PPi, from its metabolism in normal and fibrotic livers, to its protective effects on vascular calcification, using several preclinical mouse models; 2) to determine the predictive role of plasma PPi on the progression of arterial calcifications in a cohort of patients with severe liver fibrosis. To address the first aim, four mouse models of MetS (mice fed western-diet, STAM mice, ApoE-KO and Ldlr-KO mice) will be used to characterize in vivo and ex vivo the association between liver disease, PPi metabolism, and CV calcification. Then, the CV impact of administrating PPi or the TNAP inhibitor SBI-425 will be determined. The second aim will be addressed using a cohort of patients waiting for liver transplantation. Plasma PPi levels will be measured before and after liver transplantation, and associations with liver disease progression, serum propensity to calcify and vascular calcium score will be determined.