Linking the DNA Damage Response and Calcification of Arteries

Researchers here provide evidence for a specific mechanism that can link the oxidative stress of aging with calcification of tissues such as arteries. Calcification reduces elasticity, which in the case of blood vessels contributes to hypertension, but it can also cause serious functional issues in other tissues. Oxidative molecules are generated in increasing numbers in aged tissues, and where their presence outweighs the existing antioxidant defenses over the long term, disruption results. The deeper causes of this oxidative stress include chronic inflammation, such as that produced by senescent cells, and mitochondrial dysfunction. As the example here shows, the consequent disruptions produced by oxidative stress include maladaptive responses in the regulation of cellular behavior.

Biomineralization is the deposition of mineral particles within a proteinaceous organic matrix. In bone, this is an essential physiological process, but extensive pathological calcification of soft tissues, in particular the vasculature, commonly occurs in association with disease. Determining how this complex chemical process is controlled is relevant to both bone development and the treatment of detrimental conditions such as "hardening of the arteries." Despite increased understanding of the cell biological processes involved in biomineralization, the chemical mechanism of mineral nucleation remains elusive.

Studies in vitro have shown that the formation of bone-like ordered mineral deposits around collagen fibrils requires other factors such as additional or substituting mineral ions or non-collagenous biomolecules. This implies that there is cellular control of extracellular matrix (ECM) calcification through the secretion of specific factors, but the identification of these factors remains elusive. In both bone and the vasculature, biomineralization is accompanied by osteogenic differentiation of resident osteoblasts and vascular smooth muscle cells (VSMCs), respectively. Osteogenic differentiation results in increased expression of multifunctional acidic proteins, including the small integrin-binding ligand, N-linked glycoprotein (SIBLING) proteins, and speculation has focused on these "osteogenic" proteins as specialist molecules that may selectively bind calcium ions and provide specificity of interaction with collagen fibrils, these proteins do not have the calcium concentration capacity to induce collagen calcification.

Previously we discovered that poly(ADP-ribose) (PAR) is abundant in the calcifying growth plate of developing fetal bone, which led us to hypothesize that PAR may play a role in biomineralization. PAR is a post-translational modification moiety composed of sugar phosphates that is produced by PAR polymerase (PARP) enzymes and adducted to numerous cellular proteins in a process known as PARylation. Several characteristics of PAR lend support to its possible extracellular role in biomineralization: first, the pyrophosphate groups of PAR are predicted to locally bind calcium ions, potentially to the levels needed for mineral nucleation. Second, PARP1 and PARP2, the dominant PAR-producing enzymes, are expressed in response to DNA damage and oxidative stress, both etiologies associated with vascular calcification. Third, emerging evidence suggests that osteogenic differentiation in calcifying osteoblasts is regulated by PARP activity induced by hydrogen peroxide release from cells. Therefore, we explored whether PAR could control the physicochemical process of mineral formation in the ECM and provide evidence that PAR biosynthesis, induced in part by the cellular DNA damage response (DDR), is a unifying factor in physiological bone and pathological artery calcification.


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