Cell Death, Damage-Associated Molecular Patterns, and Sterile Inflammation in Cardiovascular Disease

Abstract

Abstract-Cell death and inflammation are ancient processes of fundamental biological importance in both normal physiology and pathology. This is evidenced by the profound conservation of mediators, with ancestral homologues identified from plants to humans, and the number of diseases driven by aberrant control of either process. Apoptosis is the most well-studied cell death, but many forms exist, including autophagy, necrosis, pyroptosis, paraptosis, and the obscure dark cell death. Cell death occurs throughout the cardiovascular system, from initial shaping of the heart and vasculature during development to involvement in pathologies, including atherosclerosis, aneurysm, cardiomyopathy, restenosis, and vascular graft rejection. However, determining whether cell death primarily drives pathology or is a secondary bystander effect is difficult. Inflammation, the primary response of innate immunity, is considered essential in initiating and driving vascular diseases. Cell death and inflammation are inextricably linked with their effectors modulating the other process. Indeed, an evolutionary link between cell death and inflammation occurs at caspase-1 (which activates interleukin-1␤), which can induce death by pyroptosis, and is a member of the caspase family vital for apoptosis. This review examines cell death in vascular disease, how it can induce inflammation, and finally the emergence of inflammasomes in vascular pathology. (Arterioscler Thromb Vasc Biol. 2011;31:2781-2786.)

Sex- and Disease-Specific Inflammasome Signatures in Circulating Blood Leukocytes of Patients with Abdominal Aortic Aneurysm

“…Whether these adventitia-infiltrating immune cells are derived from peripheral blood cells that invaded the tissue, and whether inflammasome activation occurred before or after tissue infiltration remain to be investigated. There is clear evidence that cell death can activate innate immunity via inflammasomes and result in sterile imflammation also in the vasculature (27). Possibly, necrotic cells from the aneurysm wall release intracellular material, which triggers inflammasome activation via the dsDNA sensor AIM2 and invasion of immune cells from the peripheral blood.…”

Effects of interleukin-1 on cardiac fibroblast function: Relevance to post-myocardial infarction remodelling

“…Although cardiomyocytes undergo rapid necrotic cell death in response to ischaemia, CF appear to be less sensitive to oxygen and nutrient starvation (Zhang et al, 2001) and could therefore be important sensors of early cardiomyocyte damage. The close positioning of myocytes and fibroblasts in the heart, coupled with recent evidence that CF express components of the innate immune system including Toll-like receptors and NOD-like receptors (Strand et al, 2013;Fernandez-Velasco et al, 2012), suggests that fibroblasts are able to rapidly sense endogenous danger signals known as damage-associated molecular patterns (DAMPs) that occur following myocyte damage and necrosis (Arslan et al, 2011;Zheng et al, 2011).…”

Statins and nonalcoholic fatty liver disease: a bright future?

“…Cholesterol esters within the necrotic core of an atheromatic plaque are related to lesion development. However, recent data suggest that crystals within very early plaques cause membrane rupture, leading to NLRP3 inflammasome activation, IL-1b release and progression of atherosclerosis [12]. As described above, IL-1b is a potent proinflammatory cytokine mainly produced by macrophages.…”

“…Inflammasome activation can also contribute to CVD pathogenesis [12]. Cholesterol esters within the necrotic core of an atheromatic plaque are related to lesion development.…”

“…During atherogenesis, chronic inflammation and infiltration of the developing plaque by monocytes lead to accumulation of macrophages. IL-1b expression is related to CVD severity, and as a mediator of the inflammatory cascade, it induces secretion of other pro-atherogenic cytokines, chemokines and endothelial expression of adhesion molecules and NO synthase (NOS) [12].…”