Age-associated pro-inflammatory remodeling and functional phenotype in the heart and large arteries

Abstract

The aging population is increasing dramatically. Aging-associated stress simultaneously drives proinflammatory remodeling, involving angiotensin II and other factors, in both the heart and large arteries. The structural remodeling and functional changes that occur with aging include cardiac and vascular wall stiffening, systolic hypertension and suboptimal ventricular-arterial coupling, features that are often clinically silent and thus termed a silent syndrome. These age-related effects are the result of responses initiated by cardiovascular proinflammatory cells. Local proinflammatory signals are coupled between the heart and arteries due to common mechanical and humoral messengers within a closed circulating system. Thus, targeting proinflammatory signaling molecules would be a promising approach to improve age-associated suboptimal ventricular-arterial coupling, a major predisposing factor for the pathogenesis of clinical cardiovascular events such as heart failure.

Keywords: Aging; Cardiovascular remodeling; Proinflammation; Ventricular–arterial coupling.

Figure 1. Impact of proinflammatory signaling on heart and arterial phenotype and ventricular-arterial coupling with advancing age

Aging increases allostatic load, including Ang II signaling, leading to proinflammation. With aging, adverse remodeling develops in both the heart and large arteries, which is the underlying mechanism of abnormal arterial-ventricular coupling. A mismatched or suboptimal arterial-ventricular mechanical coupling, sometimes known as “coupling disease”, is manifest by increases in SBP and left ventricular diastolic dysfunction. Suboptimal arterial-ventricular coupling increases the susceptibility to complications such as heart failure, atherosclerosis and stroke (sometimes termed “de-coupling diseases”), in response to pathologic stimuli such as ischemia.

Figure 2. Proinflammatory signaling mechanisms and effect of cellular phenotype during aging

Abbreviations and acronyms: Ang II: angiotensin II; Ets-1/2: the v-ets erythroblastosis virus E26 oncogene homolog 1; MMPs: matrix metalloproteases; MFG-E8: milk fat globule epidermal growth factor-8; MCP-1: monocyte chemo-attractant protein-1; NO: nitric oxide; RAAS: renin angiotensin aldosterone system; SIRT1: silent information regulation 2 homolog 1; TGF-β1: transforming growth factor β1; TNF-α: tumor necrosis factor alpha; IL; interleukin; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells. ECs: endothelial cells; VSMCs: vascular smooth muscle cells; ECM: extracellular matrix