The role of A-kinase anchoring proteins in cardiac oxidative stress.

Cardiac stress initiates a pathological remodeling process that is associated with cardiomyocyte loss and fibrosis that ultimately leads to heart failure. In the injured heart, a pathologically elevated synthesis of reactive oxygen species (ROS) is the main driver of oxidative stress and consequent cardiomyocyte dysfunction and death. In this context, the cAMP-dependent protein kinase (PKA) plays a central role in regulating signaling pathways that protect the heart against ROS-induced cardiac damage. In cardiac cells, spatiotemporal regulation of PKA activity is controlled by A-kinase anchoring proteins (AKAPs). This family of scaffolding proteins tether PKA and other transduction enzymes at subcellular microdomains where they can co-ordinate cellular responses regulating oxidative stress. In this review, we will discuss recent literature illustrating the role of PKA and AKAPs in modulating the detrimental impact of ROS production on cardiac function.

The Role of Cyclic AMP Signaling in Cardiac Fibrosis.

Myocardial stress and injury invariably promote remodeling of the cardiac tissue, which is associated with cardiomyocyte death and development of fibrosis. The fibrotic process is initially triggered by the differentiation of resident cardiac fibroblasts into myofibroblasts. These activated fibroblasts display increased proliferative capacity and secrete large amounts of extracellular matrix. Uncontrolled myofibroblast activation can thus promote heart stiffness, cardiac dysfunction, arrhythmias, and progression to heart failure. Despite the well-established role of myofibroblasts in mediating cardiac disease, our current knowledge on how signaling pathways promoting fibrosis are regulated and coordinated in this cell type is largely incomplete. In this respect, cyclic adenosine monophosphate (cAMP) signaling acts as a major modulator of fibrotic responses activated in fibroblasts of injured or stressed hearts. In particular, accumulating evidence now suggests that upstream cAMP modulators including G protein-coupled receptors, adenylyl cyclases (ACs), and phosphodiesterases (PDEs); downstream cAMP effectors such as protein kinase A (PKA) and the guanine nucleotide exchange factor Epac; and cAMP signaling organizers such as A-kinase anchoring proteins (AKAPs) modulate a variety of fundamental cellular processes involved in myocardial fibrosis including myofibroblast differentiation, proliferation, collagen secretion, and invasiveness. The current review will discuss recent advances highlighting the role of cAMP and AKAP-mediated signaling in regulating pathophysiological responses controlling cardiac fibrosis.

A-Kinase Anchoring Protein-Lbc: A Molecular Scaffold Involved in Cardiac Protection.

Heart failure is a lethal disease that can develop after myocardial infarction, hypertension, or anticancer therapy. In the damaged heart, loss of function is mainly due to cardiomyocyte death and associated cardiac remodeling and fibrosis. In this context, A-kinase anchoring proteins (AKAPs) constitute a family of scaffolding proteins that facilitate the spatiotemporal activation of the cyclic adenosine monophosphate (AMP)-dependent protein kinase (PKA) and other transduction enzymes involved in cardiac remodeling. AKAP-Lbc, a cardiac enriched anchoring protein, has been shown to act as a key coordinator of the activity of signaling pathways involved in cardiac protection and remodeling. This review will summarize and discuss recent advances highlighting the role of the AKAP-Lbc signalosome in orchestrating adaptive responses in the stressed heart.

Small-Molecule Protein-Protein Interaction Inhibitor of Oncogenic Rho Signaling.

Uncontrolled activation of Rho signaling by RhoGEFs, in particular AKAP13 (Lbc) and its close homologs, is implicated in a number of human tumors with poor prognosis and resistance to therapy. Structure predictions and alanine scanning mutagenesis of Lbc identified a circumscribed hot region for RhoA recognition and activation. Virtual screening targeting that region led to the discovery of an inhibitor of Lbc-RhoA interaction inside cells. By interacting with the DH domain, the compound inhibits the catalytic activity of Lbc, halts cellular responses to activation of oncogenic Lbc pathways, and reverses a number of prostate cancer cell phenotypes such as proliferation, migration, and invasiveness. This study provides insights into the structural determinants of Lbc-RhoA recognition. This is a successful example of structure-based discovery of a small protein-protein interaction inhibitor able to halt oncogenic Rho signaling in cancer cells with therapeutic implications.

Mixed infection of peste des petits ruminants virus (PPRV) and other respiratory viruses in dromedary camels in Sudan, an abattoir study.

This study was intended to determine the role played by peste des petits ruminants (PPR) in causing respiratory infections in camels and its association with other respiratory viruses. A total of 474 lung specimens showing pneumonia were collected from clinically healthy camels in slaughterhouses at five different areas in Sudan. Using immunocapture ELISA (IcELISA), 214 specimens (45.1 %) were found to be positive for PPR antigen. The highest prevalence was found in central Sudan (59.9 %) then northern Sudan (56.6 %) and eastern Sudan (26.6 %). Parainfluenza virus 3 (PIV 3), respiratory syncytial virus (RSV), bovine herpes virus-1 (BHV-1), bovine viral diarrhea (BVD), and adenovirus were detected in 4.4, 2.9, 2.0, 9.0, and 1.3 % of the specimens, respectively. PPR antigen was found in about 50 % of specimens that showed positive result for other viral antigens. Twenty-five of 28 BVD, 15 of 16 PIV3, 8 of 12 RSV, 4 of 4 adenovirus, and 4 of 5 BHV-1 were found in association with other respiratory antigens. Results revealed the existence of PPRV infection in dromedary camels in Sudan and present evidence for mixed virus infection, suggesting that respiratory infections in camels might be exacerbated by PPRV.

Asian lineage of peste des petits ruminants virus, Africa.

Interest in peste des petits ruminants virus (PPRV) has been stimulated by recent changes in its host and geographic distribution. For this study, biological specimens were collected from camels, sheep, and goats clinically suspected of having PPRV infection in Sudan during 2000-2009 and from sheep soon after the first reported outbreaks in Morocco in 2008. Reverse transcription PCR analysis confirmed the wide distribution of PPRV throughout Sudan and spread of the virus in Morocco. Molecular typing of 32 samples positive for PPRV provided strong evidence of the introduction and broad spread of Asian lineage IV. This lineage was defined further by 2 subclusters; one consisted of camel and goat isolates and some of the sheep isolates, while the other contained only sheep isolates, a finding with suggests a genetic bias according to the host. This study provides evidence of the recent spread of PPRV lineage IV in Africa.