CALCIFICATION IN THE CARDIOVASCULAR SYSTEM

心脏病是造成死亡、残疾和经济损失的主要原因。

Heart diseases are a major cause of death, disability and economic los. Often, heart conditions coincide with blood vessel blockage by calcified plaques. The overall objective is to develop sufficient information on the kinetic and structural properties of cardiovascular deposits (CD) and on the inhibition mechanisms of agents that can prevent formation of CD. We propose to: I. Assess the therapeutic potential of various novel phosphonate drugs for control of formation and growth of calcified deposits by in vitro experiments of spontaneous precipitation and seeded growth of calcium phosphate. I. Study the inhibitory effects of drugs on dissolution and hydrolysis of OCP in order to investigate the potential of the drugs to stabilize cardiovascular calcification precursors and inhibit the transformation of the precursors to hydroxyapatite, the main constituent of CD. III. Follow the formation of precursors in vivo in the early stages of mineralization and study the inhibition effect of novel phosphonates on their formation and transformation by detection (32P- pyrolysis technique) of acidic phosphate ions (HPO4) in calcified deposits formed on subcutaneously implanted Bovine pericardium in rats. IV. Measure the dissolution and hydrolysis of OCP-carbonates under physiological conditions. Formation of OCP-CO3 and its transformation to carbonate apatite similar to CD has been proposed as an alternative mechanism for incorporation of carbonate into CD via OCP-CO3 intermediate. V. Investigate in vitro the mechanism of crystal growth on CD retrieved from patients by seeding supersaturated solutions of calcium phosphate with native and deproteinated CD powders. VI. Study the inhibition of calcium phosphate growth on CD in vitro in order to determine the effect of known bisphosphonates on crystal growth on mature CD. VII. Study the mechanism of incorporation of fluoride into CD by following the uptake of fluoride by CD and comparing with uptake by proposed precursors. The ultimate goal is to understand the process of cardiovascular calcification and to develop therapeutic treatments for atherosclerosis and prevention of the destruction of implanted bioprostheses.