Myeloid FoxO in Atherosclerosis (p 992)
Atherosclerosis worsens when macrophages lack FoxO proteins, report Tsuchiya et al.
Atherosclerosis is a leading cause of death in patients with type 2 diabetes. But exactly how high blood sugar and insulin resistance are linked to the development of atherosclerosis is unclear. It is known that insulin signaling in myeloid cells, such as macrophages, is mediated by a family of transcription factors called FoxO. Given that macrophages are a principle cell type in atherosclerotic plaques, Tsuchiya and colleagues removed FoxO factors from these cells and examined the effect on atherogenesis. They found that atherosclerosis-prone mice lacking FoxO factors in their myeloid cells had larger plaques that contained increased numbers of macrophages. The cause of this amplified lesion formation appeared to be bipartite: First, increased proliferation and decreased apoptosis contributed to the overabundance of myeloid cells in the lesion. And second reactive oxygen species, which are known to accelerate atherogenesis, were more abundant in the FoxO-lacking cells. Importantly, Tsuchiya et al showed that treating these mice with an antioxidant decreased myeloid cell numbers and lesion formation. Further studies on FoxO could aid in the design of effective anti-atherosclerosis treatments for diabetic patients.
LTC4, Orai3, and Neointimal Hyperplasia (p 1013)
Gonzalez-Cobos et al identify a potential new target to stop neointima formation.
Unlike cardiac and skeletal muscle cells, vascular smooth muscle cells (VSMCs) are not terminally differentiated. Instead, they retain the ability to proliferate and migrate when necessary, such as when blood vessels require regrowth after an injury. However, VSMC proliferation and migration can sometimes lead to an overgrowth of the cells, which may contribute to neointima formation, atherosclerosis or other vascular problems. This switch from a resting to a proliferative and migratory phenotype has been associated with the upregulation of calcium channel component Orai1, and inhibiting Orai1 upregulation has been shown to prevent neointima formation in mice. The bad news, however, is that Orai1 functions in multiple cell types, making it a non-specific target for potential therapies. Gonzales-Cobos and colleagues thus investigated Orai 3, a lesser-known homologue of Orai1. They found that, like Orai1, Orai3 was upregulated in proliferative and migratory VSMCs, but, it created an alternative form of calcium channel. Even though the channels differed, the effect of suppressing Orai3 expression in mice was the same, that is, neointima formation was prevented. Thus, for neointima-directed therapies, Orai3 may prove to be a better target than the ubiquitous Orai1.
VSMC Phenotype Modulation and Arterial Stiffness (p 1035)
To avoid age-related cardiovascular problems, vascular smooth muscle cells need to stay relaxed say Galmiche et al.
As we age our arteries tend to stiffen, which can accelerate the process of cardiovascular degeneration. This vessel stiffening has been largely attributed to changes in the extracellular matrix of the arterial wall. But recent observations suggest that vascular smooth muscle cells (VSMC) surrounding the blood vessels also stiffen with age. To study the effect of changes in VSMC stiffness in living mice Galmiche and colleagues increased and decreased the expression of serum response factor (SRF) in these cells. SRF is a transcription factor that is expressed in many cell types. In VSMCs, however, it controls the expression of cytoskeletal and contractile proteins. The team found that mice lacking SRF in VSMCs exhibited lower blood pressure and higher elasticity of the carotid artery than wild type mice. While this increase in elasticity was related to the expected decrease in the expression of contractile and cytoskeletal proteins, it was also linked to a weaker interaction between the VSMCs and the extracellular matrix. Mice over-expressing SRF in their VSMCs, on the other hand, showed increased VSMC contractility. These findings suggest that VSMCs could be an important target for preventing age-related arterial stiffness and the problems that go along with it.
- © 2013 American Heart Association, Inc.