Peptide Interference of CaM–Cyclin E Interactions (p 1053)
Hui et al have designed a small peptide that could help prevent restenosis after angioplasty.
Following angioplasty to fix a narrowing artery, it is often the case that renarrowing, or restenosis, occurs. A major cause of restenosis is the proliferation of vascular smooth muscle cells (VSMCs). Preventing such proliferation has, thus, been considered a promising avenue of therapeutic investigation. Because their research suggested that VSMC proliferation depends on the binding of calmodulin to cyclin E, Hui et al designed a peptide that would inhibit this interaction. When this 22-amino acid peptide, based on the calmodulin binding sequence of cyclin E, was transfected into VSMCs, it inhibited cell cycle progression. The team initially electroporated the peptide into cells, but once they had established its success, they switched to a therapeutically feasible delivery system—fusing their peptide to the TAT protein of human immunodeficiency virus, which enters cells with high efficiency. The TAT fusion peptide not only stopped proliferation of mouse and human cells in culture, it also limited neointima formation (vessel wall thickening) in a mouse model of arterial injury. The authors suggest that such a fusion peptide could be introduced at the time of angioplasty in the form of a drug-eluting stent and, thus, prevent local VSMC proliferation for a prolonged period of time.
Primary Cilia and Shear-Induced EndoMT (p 1093)
The presence of primary cilia prevents vascular endothelial cells from switching to a mesenchymal fate, report Egorova et al.
Primary cilia are thought to function as mechanosensors for cells. Indeed, vascular endothelial cells (ECs) maintain their primary cilia in areas that are prone to blood flow oscillations, and these cilia are lost in cells exposed to consistently high blood flow. This lack of primary cilia corresponds with the transdifferentiation of ECs into mesenchymal cells during the so-called endothelial-to-mesenchymal transition (EndoMT). Exactly how the absence of cilia is related to EndoMT, however, was unclear. Egorova et al looked at mutant ECs lacking cilia and found that they readily underwent shear stress-induced EndoMT, whereas wild-type, ciliated ECs did not. The team also showed that this EndoMT was dependent on increased signaling by tumor growth factor (TGF)-β, as well as downregulation of the transcription factor Klf4 within the ECs. Blocking TGF-β, overexpressing Klf4, or indeed restoring the primary cilia by replacing the mutant protein prevented EndoMT. The authors suggest that the fact that ECs change their fate in the absence of primary cilia may provide clues to the cardiovascular defects often associated with ciliopathies.
Calcifying Cells and Diabetic Vasculopathy (p 1112)
Fadini et al have named and shamed cellular culprits of vascular calcification.
Vascular calcification, which causes blood vessel stiffness and can destabilize atherosclerotic plaques, is a hallmark process of diabetic vasculopathy. The mechanisms underlying calcification are not well understood, but a type of circulating cell with osteoblastic (bone- forming) characteristics has been identified as the potential culprit. Fadini et al have now confirmed this suspicion by showing the procalcific activity of these cells both in vitro and in vivo. They also discovered that the cells expressed markers specific to the myeloid lineage, and so they gave them the name myeloid calcifying cells (MCCs). Interestingly, MCCs were present in higher numbers in the bone-marrow, blood, and surgically removed atherosclerotic plaques of diabetic patients vs controls. But importantly, the high numbers of circulating MCCs could be reduced to near normal levels in diabetic patients after three months of monitored glucose control (insulin plus oral agents). MCC numbers were also high in nondiabetic patients with cardiovascular disease. Hence, it is possible that targeting procalcific MCCs could be a useful therapy for preventing cardiovascular problems in high-risk individuals, whether diabetic or not.
Written by Ruth Williams
- © 2011 American Heart Association, Inc.