AKAP150 in LQT8 (p 255)
Cheng et al propose a way to combat arrhythmias in Timothy syndrome.
A mutation in the cytoplasmic loop of calcium channel protein, Cav1.2a, is known to cause Timothy syndrome, which is characterized by structural heart defects, arrhythmia, and autism spectrum disorders. The disease is also known as long QT syndrome 8, because it is associated with a prolonged depolarization-to-repolarization (QT) interval. It is not clear how the mutation causes channel dysfunction, but Cheng et al wondered if interaction with a cytoplasmic anchor protein called AKAP150 may be involved. They made transgenic mice that expressed the mutant channel and lacked AKAP150, and found these mice were protected from cardiac hypertophy and arrhythmia. In vitro analysis revealed that mutant channels functioned normally in the absence of AKAP150. The anchor appears to stabilize the mutant channels in the open configuration and might also promote clusters of mutant channels to open together – both of which would increase calcium influx and thus delay repolarization. In short, the removal of the perfectly normal AKAP150 protein fixed arrhythmias caused by the mutant Cav1.2a. When it comes to possible therapies, say the authors, disrupting the interaction between these two proteins might be sufficient.
PGF Regulates Cardiac Adaptation (p 272)
Placental growth factor helps stressed hearts to adapt, report Accornero et al.
Despite its name, placental growth factor (PGF) is found in many tissues, including the heart. PGF is elevated in human heart tissue and in cultured cardiomyocytes under low oxygen conditions. It is also elevated in the blood of patients after heart attack or during ischemic cardiomyopathy. Accornero et al also wanted to know the role of PGF in such stress conditions. The team made mice that overexpressed PGF in cardiomyocytes, and compared the effect of heart stress in these mice with wild type mice and with mice that lacked PGF. When the hearts of these mice were subjected to pressure overload, the animals overexpressing PGF exhibited greater cardiac capillary growth, fibroblast proliferation and cardiomyocyte hypertrophy, and were protected from heart failure. On the other hand, mice that lacked PGF died of heart failure within a week. Even though the extra PGF was produced by cardiomyocytes, it was the capillary cells and fibroblasts that were directly affected, while cardiomyocyte hypertrophy was a secondary response. The protective effect of PGF may make it a useful therapeutic agent but the authors caution that trials with PGF's close cousin VEGF for ischemic heart disease have yet to show promise.
Antiangiogenic VEGF165b in Systemic Sclerosis (p e14)
Manetti et al suggest a way to boost blood vessel renewal in patients suffering from scleroderma.
Scleroderma is a rare and devastating autoimmune disease that is characterized by widespread fibrosis and vascular damage. The chronic vessel damage causes tissue ischemia, which would normally lead to the production of proangiogenic factors. Paradoxically, scleroderma patients have high levels of a known proangiogenic factor, VEGF, but angiogenesis is still impaired. Manetti et al have recently worked out why. They found that scleroderma patients produce a variant of VEGF (VEGF165b) that is antiangiogenic. This variant, which is produced by alternative splicing, was discovered only recently, and previous studies of patient tissues had not differentiated between this variant and its proangiogenic form. A splicing factor called SRp55, known to drive production of VEGF165b, was also upregulated in these patients. And both SRp55 and VEGF165b were upregulated by TGF-β1. TGF-β1 is known to promote fibrosis in scleroderma patients. Thus, the new data suggests TGF-β1 drives the vascular damage as well. Lastly, the team showed that blocking VEGF165b could stimulate angiogenesis in patient-derived vascular cells, so the hope is that such an approach might also work in patients.
Written by Ruth Williams
- © 2011 American Heart Association, Inc.