Proinflammation: the key to arterial aging

Abstract

Arterial aging is the major contributing factor to increases in the incidence and prevalence of cardiovascular disease, due mainly to the presence of chronic, low-grade, 'sterile' arterial inflammation. Inflammatory signaling driven by the angiotensin II cascade perpetrates adverse age-associated arterial structural and functional remodeling. The aged artery is characterized by endothelial disruption, enhanced vascular smooth muscle cell (VMSC) migration and proliferation, extracellular matrix (ECM) deposition, elastin fracture, and matrix calcification/amyloidosis/glycation. Importantly, the molecular mechanisms of arterial aging are also relevant to the pathogenesis of hypertension and atherosclerosis. Age-associated arterial proinflammation is to some extent mutable, and interventions to suppress or delay it may have the potential to ameliorate or retard age-associated arterial diseases.

Keywords: angiotensin II; atherosclerosis; central arterial aging; hypertension; proinflammation.

Figure 1. Diagram of age-associated proinflammatory arterial remodeling

The chronic proinflammatory profile within aged central arteries is characterized by alterations in signaling systems that include Ang II signaling via its receptor AT1, as well as MR, and ET-1/ET_A signaling. AGEs recruit inflammatory molecules by interaction with their cellular transduction receptor for AGEs (RAGE). NF-κB and Ets-1 are activated within the aging arterial wall, whereas protective factors such as Nrf-2 are reduced. Downstream signaling molecules include MFG-E8, MMPs, calpain-1, MCP-1 and TGF-β1. Activation of calpain-1, MMPs, TGF-β1, NADPH oxidase increases whereas NO bioavailability decreases with advancing age. Old VSMCs secrete increased amounts of MFG-E8, MCP-1, MMP-2 and TGF-β1 and concurrent proinflammatory proliferation, migration, secretion, senescence, and extracellular matrix deposition within the aged arterial wall is observed. Disruption of the endothelium, intima-media thickening, arterial amyloidosis, fibrosis, calcification, elastin fracture, and matrix glycoxidative modifications are consequences of the enhanced signaling via these receptor signaling cascades. Some can lead to changes in arterial clinical phenotype that can be measured non-invasively in humans. A significant interaction exists between aging and hypertension and the frequency of arterial atherosclerosis markedly increases in old vs. young humans. Abbreviations: Angiotensin II: Ang II, aldosterone/mineralocorticoid receptor: MR, endothelin-1: (ET-1), endothelin-1 receptor A: ET_A, Nuclear factor kappa-light-chain-enhancer of activated B cells: NF-κB, v-ets erythroblastosis virus E26 oncogene homolog 1: Ets-1, NF-E2-related factor 2: Nrf-2, milk fat globule epidermal growth factor-8: MFG-E8, matrix metalloproteases: MMPs, monocyte chemo-attractant protein-1: MCP-1, transforming growth factor β1: TGF-β1, nicotinamide adenine dinucleotide phosphate-oxidase: NADPH oxidase, nitric oxide: NO, age-associated arterial secretory phenotype: AAASP.