calcification-vascular-smooth-muscle-cells-imaging-aortic

Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation

Cardiovascular disease is the leading cause of morbidity and mortality in the world.  Atherosclerotic plaques, consisting of lipid-laden macrophages and ...

Massachusetts General Hospital

Parents defend their young in many ways, including provisioning chemical defences. Recent work in a poison frog system offers the first example of an animal that provisions its young with alkaloids after hatching or birth rather than before. But it is not yet known whether maternally derived alkaloids are an effective defence against offspring predators. We identified the predators of Oophaga pumilio tadpoles and conducted laboratory and field choice tests to determine whether predators are deterred by alkaloids in tadpoles. We found that snakes, spiders and beetle larvae are common predators of O. pumilio tadpoles. Snakes were not deterred by alkaloids in tadpoles. However, spiders were less likely to consume mother-fed O. pumilio tadpoles than either alkaloid-free tadpoles of the red-eyed treefrog, Agalychnis callidryas, or alkaloid-free O. pumilio tadpoles that had been hand-fed with A. callidryas eggs. Thus, maternally derived alkaloids reduce the risk of predation for tadpoles, but only against some predators.

Maternally derived chemical defences are an effective deterrent against some predators of poison frog tadpoles (Oophaga pumilio).

Iron homeostasis is tightly regulated by the membrane iron exporter ferroportin and its regulatory peptide hormone hepcidin. The hepcidin/ferroportin axis is considered a promising therapeutic target for the treatment of diseases of iron overload or deficiency. Here, we conducted a chemical screen in zebrafish to identify small molecules that decrease ferroportin protein levels. The chemical screen led to the identification of 3 steroid molecules, epitiostanol, progesterone, and mifepristone, which decrease ferroportin levels by increasing the biosynthesis of hepcidin. These hepcidin-inducing steroids (HISs) did not activate known hepcidin-inducing pathways, including the BMP and JAK/STAT3 pathways. Progesterone receptor membrane component-1 (PGRMC1) was required for HIS-dependent increases in hepcidin biosynthesis, as PGRMC1 depletion in cultured hepatoma cells and zebrafish blocked the ability of HISs to increase hepcidin mRNA levels. Neutralizing antibodies directed against PGRMC1 attenuated the ability of HISs to induce hepcidin gene expression. Inhibiting the kinases of the SRC family, which are downstream of PGRMC1, blocked the ability of HISs to increase hepcidin mRNA levels. Furthermore, HIS treatment increased hepcidin biosynthesis in mice and humans. Together, these data indicate that PGRMC1 regulates hepcidin gene expression through an evolutionarily conserved mechanism. These studies have identified drug candidates and potential therapeutic targets for the treatment of diseases of abnormal iron metabolism.

Georgia Shelton

Massachusetts General Hospital

Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation