Study proposes a final common pathway linking smoking, kidney disease, and inflammation to atherogenesis
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October 17, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [1]
Cleveland, OH: Scientists from the Cleveland Clinic have proposed a post-translational modification of proteins called carbamylation as a common mechanism of vascular dysfunction in patients with various coronary artery disease risk factors. While most physicians have not considered the metabolism of cyanate since they memorized the urea cycle in medical school, researchers have been studying the addition of this molecule to proteins (i.e. carbamylation) for years in kidney disease patients. Patients with kidney disease have excess urea, which is in equilibrium with cyanate. Protein carbamylation can alter protein function and structure, and is thought to represent one of the toxic products of uremia. The authors provide evidence that the protein myeloperoxidase, the enzyme in neutrophils that catalyzes the “respiratory burst” needed to kill bacterial, can also generate cyanate from thiocyanate, a molecule found in high levels in smokers. They show that myeloperoxidase acts in vivo to promote protein carbamylation of LDL, making LDL more atherogenic. These results link inflammation, uremia, and smoking as having a common final mechanism of atherogenesis.
The major amino acid residue which is carbamylated in vivo is lysine, forming e-carbamyllysine, also known as homocitrulline (HCit). The authors developed a new method for assessing protein carbamylation by measuring HCit content of proteins by mass spectrometry. They demonstrate that neutrophil myeloperoxidase can facilitate carbamylation of proteins by forming cyanate from thiocyanate ions. Thiocyanate levels are higher in smokers and are very influenced by diet, forming a connection between smoking, diet, and inflammation. The authors first demonstrate that myeloperoxidase contributes to protein carbamylation in vivo. They show that mice deficient in myeloperoxidase have reduced protein carbamylation during inflammation and that protein carbamylation is higher in atherosclerotic plaques of mice that overexpress myeloperoxidase. Additionally, the authors demonstrate that myeloperoxidase co-localizes with carbamylated protein in human atheromas. Next, they provide evidence that carbamylated LDL is atherogenic. They show that after acted upon by myeloperoxidase, LDL does not bind to the LDL receptor as well and it promotes macrophage foam cell formation. Finally, the authors demonstrated a correlation between HCit quartile and cardiovascular risk in a small retrospective case-control study.
The hypothesized role of protein carbamylation in atherogenesis is appealing for its ability to unify disparate coronary artery disease risk factors by a final common mechanism of disease. The authors provide convincing evidence from in vitro and in vivo studies that myeloperoxidase has a major role in protein carbamylation. The case-control analysis raises hope that this protein modification might serve as a marker of cardiovascular risk, or as a target for cardiovascular therapeutics in the future. Future work should examine this protein modification in a larger population with multivariate analyses to determine whether high plasma HCit is an independent coronary disease risk factor, or whether it is explained by other known risk factors (smoking, dyslipidemia, renal disease) that might alter levels of HCit.
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