MEF2 Activity and Apelin-APJ (p 22)
Kang et al uncover the role of apelin-APJ signaling in mammalian cardiovascular development.
The small peptide ligand apelin and its receptor APJ are known to be involved in cardiovascular development in both frogs and fish. Surprisingly, the role of apelin-APJ in mammalian cardiovascular development remains unknown. Kang et al studied mice that had homozygous null alleles of the Apj gene, most of whom die as embryos between stage E10.5 and E12.5 of embryogenesis. They found that the mutant mouse embryos exhibited a broad spectrum of cardiovascular developmental abnormalities, including particular blood vessels that were either poorly developed or entirely missing, and hearts that were malformed. Even the few mice—less than 10 percent—that survived into adulthood showed significant heart malformations, including enlarged right ventricles and septal defects. Apelin-APJ regulates the expression of the transcription factor KLF2, and the team showed that this occurs via activation of another transcription factor - MEF2, a known activator of KLF2. The critical importance of apelin-APJ signaling in mammalian cardiovascular development suggests that the ligand and its receptor could be a focus for study in humans with congenital heart abnormalities, the authors say.
Endothelial MiR-126 and SMC Turnover (p 40)
MicroRNA-126 promotes smooth muscle cell turnover and the progression of atherosclerotic lesions, say Zhou et al.
Vascular smooth muscle cells (VSMCs) are generally quiescent in adult blood vessels but can be sparked back into a proliferative state both in atherosclerotic lesions and during vessel injury, where they promote angiogenesis leading to an increase in angiogenesis. The microRNA miR-126 is a regulator of angiogenesis and it is produced by endothelial cells (ECs). Given the proximity of ECs to SMCs in vessel walls, Zhou and colleagues wondered whether miR-126 might promote angiogenic behavior in SMCs. And It did. They found that SMCs cultured with ECs exhibited higher levels of proliferation, and this increase was mitigated when miR-126 was blocked in the ECs. Interestingly, ECs exposed to laminar sheer stress did not secrete as much miR-126 as those exposed to an oscillatory fluid flow, which is known to promote atherogenesis in blood vessels. Indeed, endothelial material extracted from mouse arterial regions associated with oscillatory flow and atherosclerotic lesions had a 3-fold higher level of miR-126 expression than arterial regions experiencing lamina flow. These results provide at least a partial explanation of why oscillatory flow promotes atherosclerosis, and may offer clues to stop SMCs from undergoing pathological proliferation.
ADAM17 and CD36-Mediated Apoptotic Cell Uptake (p 52)
Deleting the protease ADAM17 helps macrophages clear up inflammation, report Driscoll et al.
Clearing up the remains of apoptotic cells is essential for wound healing and for the resolution of inflammation. Indeed, dysfunctional cell clearance is commonly observed in chronic inflammatory disorders. Macrophages do most of this work, using receptors on their cell surface to recognize, and trigger phagocytosis of apoptotic cells. However, the receptors can be proteolytically cleaved from macrophages, and this has been offered as one reason why levels of soluble receptors are increased in the tissue fluids during inflammation. To investigate this phenomenon more closely, Driscoll and colleagues deleted ADAM17 - a protease known to cleave cell surface receptors involved in inflammation—from macrophages in mice. Following induced inflammation, the team observed that phagocytosis of apoptotic cells was increased in mice with ADAM17-null macrophages, and that inflammation resolved more quickly. They also identified CD36 as the cell surface receptor targeted by ADAM17, showing that soluble CD36 levels were reduced in media incubated with ADAM17-null macrophages compared with wildtype macrophages. This work provides a new explanation of why soluble CD36 levels are increased in many chronic inflammatory conditions, and these findings may also provide additional avenues for resolving inflammation.
- © 2013 American Heart Association, Inc.