No abstract

Pertussis toxin (PTX) is a typical A-B toxin. The A-protomer (S1 subunit) exhibits ADP-ribosyltransferase activity. The B-oligomer consists of four subunits (S2 to S5) and binds extracellular molecules that allow the toxin to enter the cells. The A-protomer ADP-ribosylates the α subunits of heterotrimeric Gi/o proteins, resulting in the receptors being uncoupled from the Gi/o proteins. The B-oligomer binds proteins expressed on the cell surface, such as Toll-like receptor 4, and activates an intracellular signal transduction cascade. Thus, PTX modifies cellular responses by at least two different signaling pathways; ADP-ribosylation of the Gαi/o proteins by the A-protomer (Gi/o protein-dependent action) and the interaction of the B-oligomer with cell surface proteins (Gi/o protein-independent action).

β-Arrestin functions as a scaffold for CaMKII and the Rap guanine nucleotide exchange factor Epac to regulate signaling from β1-ARs.

In the present study, we examined signal transduction mechanism of reactive oxygen species (ROS) production and the role of ROS in angiotensin II-induced activation of mitogen-activated protein kinases (MAPKs) in rat neonatal cardiomyocytes. Among three MAPKs, c-Jun NH 2 -terminal kinase (JNK) and p38 MAPK required ROS production for activation, as an NADPH oxidase inhibitor, diphenyleneiodonium, inhibited the activation.

The beta-adrenergic receptor (betaAR) signaling system is one of the most powerful regulators of cardiac function and a key regulator of Ca(2+) homeostasis. We investigated the role of betaAR stimulation in augmenting cardiac function and its role in the activation of Ca(2+)/calmodulin-dependent kinase II (CaMKII) using various betaAR knockouts (KO) including beta(1)ARKO, beta(2)ARKO, and beta(1)/beta(2)AR double-KO (DKO) mice. We employed a murine model of left anterior descending coronary artery ligation to examine the differential contributions of specific betaAR subtypes in the activation of CaMKII in vivo in failing myocardium. Cardiac inotropy, chronotropy, and CaMKII activity following short-term isoproterenol stimulation were significantly attenuated in beta(1)ARKO and DKO compared with either the beta(2)ARKO or wild-type (WT) mice, indicating that beta(1)ARs are required for catecholamine-induced increases in contractility and CaMKII activity. Eight weeks after myocardial infarction (MI), beta(1)ARKO and DKO mice showed a significant attenuation in fractional shortening compared with either the beta(2)ARKO or WT mice. CaMKII activity after MI was significantly increased only in the beta(2)ARKO and WT hearts and not in the beta(1)ARKO and DKO hearts. The border zone of the infarct in the beta(2)ARKO and WT hearts demonstrated significantly increased apoptosis by TUNEL staining compared with the beta(1)ARKO and DKO hearts. Taken together, these data show that cardiac function and CaMKII activity are mediated almost exclusively by the beta(1)AR. Moreover, it appears that beta(1)AR signaling is detrimental to cardiac function following MI, possibly through activation of CaMKII.

Transforming growth factor-β (TGF-β) is a common mediator of cancer progression and fibrosis. Fibrosis can be a significant pathology in multiple organs, including the heart. In this review, we explain how inhibitors of TGF-β signaling can work as antifibrotic therapy. After cardiac injury, profibrotic mediators such as TGF-β, angiotensin II, and endothelin-1 simultaneously activate cardiac fibroblasts, resulting in fibroblast proliferation and migration, deposition of extracellular matrix proteins, and myofibroblast differentiation, which ultimately lead to the development of cardiac fibrosis. The consequences of fibrosis include a wide range of cardiac disorders, including contractile dysfunction, distortion of the cardiac structure, cardiac remodeling, and heart failure. Among various molecular contributors, TGF-β and its signaling pathways which play a major role in carcinogenesis are considered master fibrotic mediators. In fact, recently the inhibition of TGF-β signaling pathways using small molecule inhibitors, antibodies, and gene deletion has shown that the progression of several cancer types was suppressed. Therefore, inhibitors of TGF-β signaling are promising targets for the treatment of tissue fibrosis and cancers. In this review, we discuss the molecular mechanisms of TGF-β in the pathogenesis of cardiac fibrosis and cancer. We will review recent in vitro and in vivo evidence regarding antifibrotic and anticancer actions of TGF-β inhibitors. In addition, we also present available clinical data on therapy based on inhibiting TGF-β signaling for the treatment of cancers and cardiac fibrosis.

Although the cardioprotective effects of glucagon-like peptide-1 and its analogs have been reported, the exact mechanisms of the glucagon-like peptide-1 receptor (GLP-1R) signaling pathway in the heart are still unclear. Activation of the GLP-1R has been shown to increase cAMP levels, thus eliciting protein kinase A- and exchange protein activated by cAMP (Epac)-dependent signaling pathways in pancreatic β-cells. However, which pathway plays an important role in the antioxidant and antiapoptotic effects of GLP-1R activation in the heart is not known. In this study, we demonstrated that stimulation of GLP-1Rs with exendin-4 attenuated H2O2-induced reactive oxygen species production and increased the synthesis of antioxidant enzymes, catalase, glutathione peroxidase-1, and manganese superoxide dismutase that is dependent on Epac. Additionally, exendin-4 has an antiapoptotic effect by decreasing a number of apoptotic cells, inhibiting caspase-3 activity, and enhancing the expression of antiapoptotic protein B-cell lymphoma 2, which is mediated through both protein kinase A- and Epac-dependent pathways. These data indicate a critical role for Epac in GLP-1R-mediated cardioprotection.

The cellular antioxidant enzymes play the important role of protecting the cells and organisms from the oxidative damage. Natural antioxidants contained in fruits have attracted considerable interest because of their presumed safety and potential nutritional value. Even though antioxidant activities of many fruits have been reported, the effects of phytochemicals contained in fruits on the induction of antioxidant enzymes in the cells have not been fully defined. In this study, we showed that extracts from Antidesma ghaesembilla, Averrhoa bilimbi, Malpighia glabra, Mangifera indica, Sandoricum koetjape, Syzygium malaccense, and Ziziphus jujuba inhibited H2O2-induced intracellular reactive oxygen species production in HEK-293 cells. Additionally, these Thai fruit extracts increased the mRNA and protein expressions of antioxidant enzymes, catalase, glutathione peroxidase-1, and manganese superoxide dismutase. The consumption of Thai fruits rich in phenolic compounds may reduce the risk of oxidative stress.