Proinflammation, profibrosis, and arterial aging

Abstract

Aging is a major risk factor for quintessential cardiovascular diseases, which are closely related to arterial proinflammation. The age-related alterations of the amount, distribution, and properties of the collagen fibers, such as cross-links and degradation in the arterial wall, are the major sequelae of proinflammation. In the aging arterial wall, collagen types I, II, and III are predominant, and are mainly produced by stiffened vascular smooth muscle cells (VSMCs) governed by proinflammatory signaling, leading to profibrosis. Profibrosis is regulated by an increase in the proinflammatory molecules angiotensin II, milk fat globule-EGF-VIII, and transforming growth factor-beta 1 (TGF-β1) signaling and a decrease in the vasorin signaling cascade. The release of these proinflammatory factors triggers the activation of matrix metalloproteinase type II (MMP-2) and activates profibrogenic TGF-β1 signaling, contributing to profibrosis. The age-associated increase in activated MMP-2 cleaves latent TGF-β and subsequently increases TGF-β1 activity leading to collagen deposition in the arterial wall. Furthermore, a blockade of the proinflammatory signaling pathway alleviates the fibrogenic signaling, reduces profibrosis, and prevents arterial stiffening with aging. Thus, age-associated proinflammatory-profibrosis coupling is the underlying molecular mechanism of arterial stiffening with advancing age.

Keywords: aging; artery; collagen; profibrosis; proinflammation; stiffening.

Figure 1

Diagram depicting the arterial proinflammatory‐profibrosis coupling events. AGEs, advanced glycosylation end‐products; AngII, angiotensin II; AT1, Ang II type 1 receptor; CDC42, cell division control protein 42 homolog; CTGF, connective tissue growth factor; ECs, endothelial cells; HSP47, heat shock protein 47; MCP‐1, monocyte chemoattractant protein‐1; MFG‐E8, milk fat globule epidermal growth factor‐8; MMPs, matrix metalloproteinases; NADPH oxidase, nicotinamide adenine dinucleotide phosphate oxidase; NO, nitric oxide; P4H, prolyl‐4‐hydroxylase; PDI, protein‐disulfide isomerase; PKC, protein kinase C; SMADs, homologies to the Caenorhabditis elegans SMA (“small” worm phenotype) and Drosophila MAD (“Mothers Against Decapentaplegic”) family of proteins; TGF‐β1, transforming growth factor‐beta 1; VSMCs, vascular smooth muscle cells.