Arginase 1 Is Regulated by LXRα (p 492)
Pourcet et al identify a new mechanism that promotes the regression of atherosclerotic plaques.
Due to its slow life-long progression, the development of atherosclerotic plaques is difficult to control, even with optimal therapy. Therefore, attempts to promote the regression of preformed plaques are particularly attractive. Even though plaque regression is difficult to study, it has been reported that transplantation of atherosclerotic aorta from atherosclerosis-prone apoE-null mice to wild-type nonatherosclerotic mice results in plaque reduction. Using this ingenious model, Pourcet et al now show that plaque regression is accompanied by an increase in the expression of the anti-inflammatory enzyme arginase1 (Arg1). They report that that this increase is regulated by the liver X receptor alpha (LXRα) and that deletion of LXRα prevents the upregulation of Arg1 in regressive lesions. Nevertheless, LXRα did not directly bind to the Arg-1 gene; instead, it increased the expression of IRF8, which in concert with PU.1, stimulated Arg1 gene expression in macrophages. Although previous studies have shown that LXRs prevent inflammation, the work of Pourcet and colleagues reveals a new molecular pathway linking LXRs to plaque regression, raising the possibility that the pathway could be gainfully targeted to reduce inflammation in atherosclerotic lesions and to promote plaque regression.
Orai1 and Neointima Formation (p 534)
Zhang et al find a new way to prevent abnormal smooth muscle cell growth.
Although smooth muscle cells in normal blood vessels remain quiescent and contractile, disease or injury can cause these cells to change their phenotype and proliferate, thereby contributing to the formation of atherosclerotic lesions, hypertension, or restenosis after angioplasty. The processes that regulate smooth muscle cell proliferation are not fully understood; however, calcium signaling has been shown to play an essential role. Zhang et al report that Orail1, a protein involved in the generation of calcium release–activated calcium current, is required for the proliferation of smooth muscle cells in rat carotid arteries after balloon injury. They found that Orail1 levels were increased in proliferating smooth muscle cells of the injured artery and that knockdown of Orail1 decreased neointima formation. Because in cultured smooth muscle cells the knockdown of Orail prevented the nuclear translocation of the transcription factor NFAT, the authors suggest that calcium influx via Orail1 promotes cell growth by stimulating the nuclear translocation of NFAT and that Orail1 may be a new drug target for preventing abnormal smooth muscle cell growth.
Cell Senescence in Pulmonary Hypertension (p 543)
Noureddine et al say that pulmonary hypertension may be due to accelerated aging of smooth muscle cells.
Because chronic obstructive pulmonary disease (COPD) is usually diagnosed in the middle-aged or elderly, it has been long suspected to be a symptom of accelerated aging. Clarifying this relationship, Noureddine et al report that in pulmonary artery smooth muscle cells of COPD patients, the extent of telomere shortening, which is indicative of replicative senescence, is directly related to the severity of pulmonary hypertension. They found that the senescent cells were located near actively dividing cells, and, when the senescent cells were put in culture, they excreted factors that stimulated the growth of normal smooth muscle cells. Thus, not only do some cells in the lung age quickly, they also coax neighboring cells to grow. This causes thickening of the blood vessels and thereby an abnormal increase in blood pressure (pulmonary hypertension). Further understanding of the causes and consequences of pulmonary smooth muscle cell aging could lead to the development of new treatments for COPD, which, despite its status as the 4th leading cause of death in the United States, has no known cure.
Written by Aruni Bhatnagar
- © 2011 American Heart Association, Inc.