Angiotensin II and Myocardial Remodeling: Do Macrophages Hold the Key?

Increasing evidence supports the notion that an excess of angiotensin II (AngII) contributes to myocardial structural remodeling and deterioration of ventricular function in conditions of cardiac injury (i.e., pressure overload). AngII may contribute to increased permeability of intramyocardial vessels, infiltration of monocytes/macrophages, and cytokine secretion resulting in enhanced inflammation, on the one hand, and differentiation of cardiac fibroblasts into myofibroblasts, on the other hand.1 The myofibroblasts are responsible for the exaggerated production of fibrillar collagen tissue that leads to myocardial fibrosis.1 At the cellular level, the proinflammatory and profibrotic activity of AngII has been linked to its capacity to activate nuclear factor-κB in vascular cells, inflammatory infiltrating cells, and myofibroblasts.1 In this issue of the Journal, Ren et al.2 have investigated the involvement of cytosolic adaptor caspase recruitment domain 9 (CARD9), a proinflammatory protein highly expressed in macrophages, on the myocardial changes induced by chronic infusion of pressor doses of AngII or saline in wild-type and CARD9 knockout mice. The findings show that in AngII-infused animals infiltration by CARD9 positive macrophages is associated with increased production of interleukin-1β by inflammatory cells, increased expression of transforming growth factor-β and connective tissue growth factor in myofibroblasts, and exaggerated deposition of collagen type I (Figure 1). In addition, CARD9 seems to be critical for mitogen-activated protein kinase-signaling and nuclear factor-κB activation in macrophages (Figure 1). This is an elegant study that provides new information of potential relevance to further understand the mechanisms of myocardial remodeling induced by systemic AngII in the context of arterial hypertension. Additional questions arise, as should be the case for such a provocative study. Firstly, nuclear factor-κB is a redox-sensitive transcription factor that is activated by reactive oxygen species, including superoxide anion (·O2−), and AngII has been shown to increase O2− production in inflammatory cells via activation of NADPH oxidase.3 Therefore, the role of O2− in nuclear factor-κB activation in CADR9 positive macrophages deserves to be explored. Secondly, the question of how systemic AngII facilitates recruitment of extracardiac CARD9 positive macrophages into the myocardium remains to be answered, as it does the question of whether local AngII produced by the cardiac renin–angiotensin system also shares this property. This can be a matter particularly relevant because recent evidence indicates that locally produced cardiac AngII plays an important role in myocardial inflammation and fibrosis in hypertensive animals.4 Finally, although the authors report that no differences were observed in cardiomyocyte apoptosis between wild-type and CARD9 knockout mice submitted to AngII infusion, no information is provided on this issue in saline-infused animals. This aspect should be further investigated taking into account that CARD9 has been shown to enhance the expression of the gene encoding the antiapoptotic Bcl-x protein and to inhibit apoptosis.5 In summary, Ren et al.2 must be congratulated for shedding new light on the molecular mechanisms of myocardial remodeling, as well as to identify CARD9 as a potential target for therapeutic antiremodeling strategies. However, more experimental data are needed to properly evaluate the role of CARD9 in the process of remodeling that accounts in different cardiac conditions. The author declared no conflict of interest.