Fbxl22, a Novel Cardiac-Enriched F-Box Protein
Spaich et al identify a novel cardiac protein that takes out the cellular trash.
The proteasome system of cells is one of the main disposal routes for misfolded or damaged proteins—an essential amenity for keeping cells clutter-free and functioning at an optimal level. While the failures of this protein turn-over system have been implicated in certain human cardiomyopathies, little is known about the components and regulators of the proteasome in cardiomyocytes. In search of novel cardiac-specific proteins, however, Spaich et al discovered Fbx122, a highly conserved component of the E3 ligase—the enzyme responsible for adding ubiquitin moieties to misfolded proteins, which tags them for destruction in the proteasome. The team discovered that not only was Fbx122 specifically expressed in the mouse heart, but it co-localized with both sarcomeric proteins and E3 ligase subunits. The team also showed that Fbx122 specifically ubiquitinated the sarcomeric proteins α-actinin and filamin C. Knockdown of Fbx122 led to the accumulation of these targets. It also led to impaired heart function and cardiomyopathy in zebrafish embryos. In both stressed cardiomyocytes and pressure-overloaded mouse hearts, Fbx122 levels decreased significantly. Whether a similar decrease in FBX122 plays a role in the development of cardiomyopathy in humans, however, is something the authors plan to investigate.
VEGF and ADAMs Mediate Collaterogenesis
Lucitti et al discover how back-up blood vessels are built in the embryonic brain.
Collaterals are blood vessels that connect one artery or arteriole to another, providing an alternative path for the supply of oxygenated blood should an artery become blocked. In adults, the extent of collateral networks—their number and size—is known to affect the outcome of ischemic tissue damage, specifically during stroke. However, surprisingly little is known about what regulates the formation of these important vessels. Thus, Lucitti et al investigated collateral development in the embryonic brain and found that their formation is restricted to a narrow window of development—between embryonic stage 13.5 and 14.5. They also discovered that collateral formation depends on the angiogenesis-promoting factor VEGF. Over-expression of VEGF prompted the growth of abundant collaterals, while embryos with low levels of VEGF, and, more specifically, embryos lacking VEGF specifically between embryonic stage 13.5 and 14.5 displayed far fewer collaterals. Importantly, these differences established in the embryo continued on into adulthood. Further understanding of collateral vessel formation could spur new therapeutic strategies for treating ischemic tissue injuries, say the authors.
APC Promotes Angiogenesis via ILK
Contrary to expectations, lack of the tumor suppressor protein APC worsens pulmonary hypertension, according to de Jesus Perez et al.
Pulmonary hypertension is characterized not only by an increase in blood pressure in the pulmonary blood vessels, but also by the loss of small pulmonary arteries. Because the Wnt/β-catenin signaling pathway is known to activate pulmonary angiogenesis, de Jesus Perez and colleagues investigated whether boosting this pathway might improve pulmonary hypertension in mice. The team studied mice that have constitutively activated β-catenin due to a lack of adenomatous polyposis coli (APC) protein, which suppresses β-catenin. Surprisingly however, these mice had more severe symptoms in response to induced pulmonary hypertension than did their normal littermate controls. It turned out that the lack of APC was actually a problem in itself. Further research revealed that pulmonary artery endothelial cells lacking APC were unable to properly adhere to extracellular matrices—specifically, laminin—and consequently started to self-destruct. Interestingly, human pulmonary artery cells also displayed low APC levels. However, transfecting these human cells with an APC-expression vector improved both laminin adherence and vessel formation in vitro. Thus, strategies that stimulate an increase in APC levels may help promote angiogenesis in pulmonary hypertension patients, say the authors.
- © 2012 American Heart Association, Inc.