ErbB signaling in cardiac development and disease.

The ErbB family of receptor tyrosine kinases (RTKs) is a family of receptors that allow cells to interact with the extracellular environment and transduce signals to the nucleus that promote differentiation, migration and proliferation necessary for proper heart morphogenesis and function. This review focuses on the role of the ErbB family of receptor tyrosine kinases, and their importance in proper heart morphogenesis, as well as their role in maintenance and function of the adult heart. Studies from transgenic mouse models have shown the importance of ErbB receptors in heart development, and provide insight into potential future therapeutic targets to help reduce congenital heart defect (CHD) mortality rates and prevent disease in adults. Cancer therapeutics have also shed light to the ErbB receptors and signaling network, as undesired side effects have demonstrated their importance in adult cardiomyocytes and prevention of cardiomyopathies. This review will discuss ErbB receptor tyrosine kinases (RTK) in heart development and disease including valve formation and partitioning of a four-chambered heart as well as cardiotoxicity when ErbB signaling is attenuated in adults.

Arsenite activates NFκB through induction of C-reactive protein.

C-reactive protein (CRP) is an acute phase protein in humans. Elevated levels of CRP are produced in response to inflammatory cytokines and are associated with atherosclerosis, hypertension, cardiovascular disease and insulin resistance. Exposure to inorganic arsenic, a common environmental toxicant, also produces cardiovascular disorders, namely atherosclerosis and is associated with insulin-resistance. Inorganic arsenic has been shown to contribute to cardiac toxicities through production of reactive oxygen species (ROS) that result in the activation of NFκB. In this study we show that exposure of the hepatic cell line, HepG2, to environmentally relevant levels of arsenite (0.13 to 2 µM) results in elevated CRP expression and secretion. ROS analysis of the samples showed that a minimal amount of ROS are produced by HepG2 cells in response to these concentrations of arsenic. In addition, treatment of FvB mice with 100 ppb sodium arsenite in the drinking water for 6 months starting at weaning age resulted in dramatically higher levels of CRP in both the liver and inner medullary region of the kidney. Further, mouse Inner Medullary Collecting Duct cells (mIMCD-4), a mouse kidney cell line, were stimulated with 10 ng/ml CRP which resulted in activation of NFκB. Pretreatment with 10 nM Y27632, a known Rho-kinase inhibitor, prior to CRP exposure attenuated NFκB activation. These data suggest that arsenic causes the expression and secretion of CRP and that CRP activates NFκB through activation of the Rho-kinase pathway, thereby providing a novel pathway by which arsenic can contribute to metabolic syndrome and cardiovascular disease.

Chronic low-level arsenite exposure through drinking water increases blood pressure and promotes concentric left ventricular hypertrophy in female mice.

Cardiovascular disease is the leading cause of death in the United States and worldwide. High incidence of cardiovascular diseases has been linked to populations with elevated arsenic content in their drinking water. Although this correlation has been established in many epidemiological studies, a lack of experimental models to study mechanisms of arsenic-related cardiovascular pathogenesis has limited our understanding of how arsenic exposure predisposes for development of hypertension and increased cardiovascular mortality. Our studies show that mice chronically exposed to drinking water containing 100 parts per billion (ppb) sodium arsenite for 22 weeks show an increase in both systolic and diastolic blood pressure. Echocardiographic analyses as well as histological assessment show concentric left ventricular hypertrophy, a primary cardiac manifestation of chronic hypertension. Live imaging by echocardiography shows a 43% increase in left ventricular mass in arsenic-treated animals. Relative wall thickness (RWT) was calculated showing that all the arsenic-exposed animals show an RWT greater than 0.45, indicating concentric hypertrophy. Importantly, left ventricular hypertrophy, although often associated with chronic hypertension, is an independent risk factor for cardiovascular-related mortalities. These results suggest that chronic low-level arsenite exposure promotes the development of hypertension and the comorbidity of concentric hypertrophy.

Viral adaptation to an antiviral protein enhances the fitness level to above that of the uninhibited wild type.

Viruses often evolve resistance to antiviral agents. While resistant strains are able to replicate in the presence of the agent, they generally exhibit lower fitness than the wild-type strain in the absence of the inhibitor. In some cases, resistant strains become dependent on the antiviral agent. However, the agent rarely, if ever, elevates dependent strain fitness above the uninhibited wild-type level. This would require an adaptive mechanism to convert the antiviral agent into a beneficial growth factor. Using an inhibitory scaffolding protein that specifically blocks phiX174 capsid assembly, we demonstrate that such mechanisms are possible. To obtain the quintuple-mutant resistant strain, the wild-type virus was propagated for approximately 150 viral life cycles in the presence of increasing concentrations of the inhibitory protein. The expression of the inhibitory protein elevated the strain's fitness significantly above the uninhibited wild-type level. Thus, selecting for resistance coselected for dependency, which was characterized and found to operate on the level of capsid nucleation. To the best of our knowledge, this is the first report of a virus evolving a mechanism to productively utilize an antiviral agent to stimulate its fitness above the uninhibited wild-type level. The results of this study may be predictive of the types of resistant phenotypes that could be selected by antiviral agents that specifically target capsid assembly.