Immunity, atherogenesis and vascular function

The session entitled Immunity, Atherogenesis and Vascular Function was presented as part of an ISN Forefronts Symposium, organized by the International Society of Nephrology (ISN) and held in in Shenzhen, China, 22–25 October 2015. The goal of the symposium was to review, update and exchange current knowledge and ideas on the pathophysiology of hypertension, vascular injury, atherogenesis and immune regulation. The symposium brought together cardiovascular physiologists, nephrologists and immunologists to promote exploration of new and innovative areas in research, as well as to encourage new and wider cross-disciplinary collaborations. Dr Andrew Newby’s review, based on his lecture at the ISN symposium, discusses how metalloproteinase from macrophages causes atherosclerotic plaque rupture and myocardial infarction (Newby, 2016). Macrophages are present at all stages of human and experimental atherosclerosis. Although widely assumed that the M1 pro-inflammatory state of macrophages can promote plaque rupture and lead to myocardial infarction, the evidence in support of this is accumulating slowly. Moreover, the important mediators of macrophage activation are uncertain, which is a barrier to the development of appropriate treatments (Stoger et al. 2012). In his presentation and review, Dr Newby highlights that plaque rupture and myocardial infarction are most likely to be the result of a ‘perfect storm’ caused by the synergistic local effects of multiple inflammatory mediators acting together in a hypoxic environment combined with the loss of anti-inflammatory factors that are responsible for an excess of matrix metalloproteinase (MMPs) over tissue inhibitors of MMP (TIMPs) expression. Dr Newby goes on to appraise critically new data pointing to the relative importance of foam cell formation as a result of lipid accumulation and the role of acquired and innate immunity and discusses the limitations of identifying precise mediators in human atherosclerosis and in animal models. Although MMP and TIMP are regulated divergently in human and mouse macrophages, production of matrix-degrading enzymes is a key feature connecting macrophage activation to plaque instability. Inflammatory mediators work through activator protein-1 and nuclear factor-B signalling pathways to regulate different MMP and TIMP expression levels. Dr Newby also reviews transcriptional and epigenetic regulation of protease production, together with recent evidence from population genetics that supports their importance. Furthermore, he addresses prospects for new therapies targeted at macrophage activation or its consequences to prevent strokes and myocardial infarctions. Dr Zhiming Zhu and colleagues provide an overview of the role of transient receptor potential (TRP) channels in the pathogenesis of hypertension and metabolic vascular damage (Zhu et al. 2016), based on Dr Zhu’s ISN symposium lecure. It is well documented that intracellular Ca2+ homeostasis is important for vascular function and blood pressure regulation, as well as for hormone secretion. Recently, TRP channels have gained attention in the field of hypertension and metabolic disorders research because of their unique roles in controlling intracellular Ca2+ concentration and vascular function. Mammalian TRP channels can be divided into six subfamilies, including TRP canonical (TRPC), TRP vanilloid (TRPV), TRP melastatin (TRPM), TRP mucolipin (TRPML), TRP ankyrin (TRPA) and TRP polycystin (TRPP). Dr Zhu and his colleagues found an increase in TRPC3 and TRPC5 channel protein expression linked to an increase in the gadolinium/calcium-influx ratio through TRPC channel activities in the monocytes and the vasculature, which are important for an elevation in blood pressure. In contrast, activation of TRPV1 and TRPM8 cause vasodilatation and a lowered blood pressure (Zhu et al. 2011). Activation of TRPV1 by capsaicin elicits release of NO from the endothelium and vasodilatation, which is inhibited by the TRPV1 antagonists. In addition, TRPM8 activation by menthol attenuates vasoconstriction and lowers blood pressure. These findings suggest