Ubiquitin ligase gene deletion attenuates diastolic dysfunction in pressure-overload hypertrophy.

Heart failure with a preserved left ventricular (LV) ejection fraction (HFpEF) often arises from a prolonged LV pressure overload (LVPO) and accompanied by abnormal extracellular matrix (ECM) accumulation. The E ubiquitin ligase WWP1 is a fundamental determinant ECM turnover. We tested the hypothesis that genetic ablation of would alter the progression of LVPO-induced HFpEF.

Nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated protein quality control in cardiomyocytes.

Protein quality control (PQC) acts to minimize the level and toxicity of malfolded proteins in the cell. It is performed by an elaborate network of molecular chaperones and targeted protein degradation pathways. PQC monitors and maintains protein homeostasis or proteostasis in the cells.

Irisin Controls Growth, Intracellular Ca2+ Signals, and Mitochondrial Thermogenesis in Cardiomyoblasts.

Exercise offers short-term and long-term health benefits, including an increased metabolic rate and energy expenditure in myocardium. The newly-discovered exercise-induced myokine, irisin, stimulates conversion of white into brown adipocytes as well as increased mitochondrial biogenesis and energy expenditure. Remarkably, irisin is highly expressed in myocardium, but its physiological effects in the heart are unknown.

Inhibitory role of reactive oxygen species in the differentiation of multipotent vascular stem cells into vascular smooth muscle cells in rats: a novel aspect of traditional culture of rat aortic smooth muscle cells.

Proliferative or synthetic vascular smooth muscle cells (VSMCs) are widely accepted to be mainly derived from the dedifferentiation or phenotypic modulation of mature contractile VSMCs, i.e., a phenotype switch from a normally quiescent and contractile type into a proliferative or synthetic form.

Deubiquitinating enzyme CYLD mediates pressure overload-induced cardiac maladaptive remodeling and dysfunction via downregulating Nrf2.

Ubiquitin proteasome system (UPS) consists of ubiquitin, ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), proteasomes, and deubiquitinating enzymes (DUBs). Ubiquitin, E1s, several E2s, E3s, and proteasomes play an important role in the regulation of cardiac homeostasis and dysfunction; however, less is known about the role of DUBs in the heart. Here, we uncovered a crucial role of cyclindromatosis (CYLD), a DUB, in mediating cardiac maladaptive remodeling and dysfunction.

Identifying panaxynol, a natural activator of nuclear factor erythroid-2 related factor 2 (Nrf2) from American ginseng as a suppressor of inflamed macrophage-induced cardiomyocyte hypertrophy.

Ethnopharmacological Relevance: American ginseng is capable of ameliorating cardiac dysfunction and activating Nrf2, a master regulator of antioxidant defense, in the heart. This study was designed to isolate compounds from American ginseng and to determine those responsible for the Nrf2-mediated resolution of inflamed macrophage-induced cardiomyocyte hypertrophy.

Materials And Methods: A standardized crude extract of American ginseng was supplied by the National Research Council of Canada, Institute for National Measurement Standards.

CYLD-mediated signaling and diseases.

The conserved cylindromatosis (CYLD) codes for a deubiquitinating enzyme and is a crucial regulator of diverse cellular processes such as immune responses, inflammation, death, and proliferation. It directly regulates multiple key signaling cascades, such as the Nuclear Factor kappa B [NFkB] and the Mitogen-Activated Protein Kinase (MAPK) pathways, by its catalytic activity on polyubiquitinated key intermediates. Several lines of emerging evidence have linked CYLD to the pathogenesis of various maladies, including cancer, poor infection control, lung fibrosis, neural development, and now cardiovascular dysfunction.

Targeting Nrf2 by dihydro-CDDO-trifluoroethyl amide enhances autophagic clearance and viability of β-cells in a setting of oxidative stress.

Nrf2 appears to be a critical regulator of diabetes in rodents. However, the underlying mechanisms as well as the clinical relevance of the Nrf2 signaling in human diabetes remain to be fully understood. Herein, we report that islet expression of Nrf2 is upregulated at an earlier stage of diabetes in both human and mice.

Nrf2 enhances myocardial clearance of toxic ubiquitinated proteins.

Nuclear factor erythroid-2 related factor 2 (Nrf2) is a master transcription factor that controls the basal and inducible expression of a battery of antioxidant genes and other cytoprotective phase II detoxifying enzymes. While knockout of Nrf2 exaggerates cardiac pathological remodeling and dysfunction in diverse pathological settings, pharmacological activation of Nrf2 protects against cardiomyocyte injury and cardiac dysfunction. In contrast, there is also a concern that the chronic activation of Nrf2 secondary to oxidative stress is a contributing mechanism for the reductive stress-mediated heart failure.

Dihydro-CDDO-trifluoroethyl amide suppresses inflammatory responses in macrophages via activation of Nrf2.

Nuclear factor erythroid 2-related factor (Nrf2) is the major regulator of cellular defenses against various pathological stresses in a variety of organ systems, thus Nrf2 has evolved to be an attractive drug target for the treatment and/or prevention of human disease. Several synthetic oleanolic triterpenoids including dihydro-CDDO-trifluoroethyl amide (dh404) appear to be potent activators of Nrf2 and exhibit chemopreventive promises in multiple disease models. While the pharmacological efficacy of Nrf2 activators may be dependent on the nature of Nrf2 activation in specific cell types of target organs, the precise role of Nrf2 in mediating biological effects of Nrf2 activating compounds in various cell types remains to be further explored.

Experimental extracorporeal photopheresis therapy significantly delays the development of diabetes in non-obese diabetic mice.

In our previous studies, we demonstrated that infusion of apoptotic cells significantly prevented type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. Extracorporeal photopheresis (ECP) is an apoptotic cell-based therapy used clinically for immune-mediated disorders. In this study, we examined the effect that intravenous delivery of apoptotic cells (ECP-treated) has in the prevention of T1D in NOD mice.

Development of a chimeric DNA-RNA hammerhead ribozyme targeting SARS virus.

Objective: Severe acute respiratory syndrome (SARS) is a severe pulmonary infectious disease caused by a novel coronavirus. To develop an effective and specific medicine targeting the SARS-coronavirus (CoV), a chimeric DNA-RNA hammerhead ribozyme was designed and synthesized using a sequence homologous with the mouse hepatitis virus (MHV).

Method: Chimeric DNA-RNA hammerhead ribozyme targeting MHV and SARS-CoV were designed and synthesized.

Innate immune responses in murine pleural mesothelial cells: Toll-like receptor-2 dependent induction of beta-defensin-2 by staphylococcal peptidoglycan.

The innate immune response is mediated in part by pattern recognition receptors including Toll-like receptors (TLRs). The pleural mesothelial cells (PMCs) that line the pleural surface are in direct contact with pleural fluid and accordingly carry the risk of exposure to infiltrating microorganisms or their components in an event of a complicated parapneumonic effusion. Here we show that murine primary PMCs constitutively express TLR-1 through TLR-9 and, upon activation with peptidoglycan (PGN), mouse PMC produce antimicrobial peptide beta-defensin-2 (mBD-2).

Receptor EphA2 activation with ephrinA1 suppresses growth of malignant mesothelioma (MM).

The objective of this study was to understand the possible mechanisms of activation of receptor EphA2 by its ligand ephrinA1 in malignant mesothelioma cell (MMC) growth. Activation of receptor EphA2 by its ligand ephrinA1 triggered the phosphorylation of EphA2. Ligand activation of EphA2 also induced phosphorylation of ERK1/2 and significantly decreased MMC proliferation.

Induction of cell cycle arrest and apoptosis by BCG infection in cultured human bronchial airway epithelial cells.

Bronchial airway epithelial cells (BAEpC) are among the first cells to encounter M. tuberculosis following airborne infection. However, the response of BAEpC to M.

Effects of leptin on endothelial function with OB-Rb gene transfer in Zucker fatty rats.

The metabolic syndrome in association with obesity is a major clinical problem inducing hypertension, diabetes mellitus, and atherosclerosis. Leptin induces angiogenesis by its proliferative effects on endothelial cells (ECs) via OB receptor (OB-Rb) gene. We evaluated the growth of ECs and intracellular signalings in response to leptin in vitro and the angiogenic effects of leptin in the cornea in vivo with and without adenovirus-mediated transfer of the OB-Rb gene in Zucker fatty (ZF) rats as a model for the metabolic syndrome.

Effect of AT2 receptor on expression of AT1 and TGF-beta receptors in VSMCs from SHR.

We recently reported that overexpression of the angiotensin II type 2 (AT2) receptor downregulates the AT1a receptor through the bradykinin/NO pathway in a ligand-independent manner in vascular smooth muscle cells (VSMCs). In the present study, we investigated the effect of AT2 receptor overexpression on the expression of the AT1a receptor and transforming growth factor-beta (TGF-beta) receptor subtypes in VSMCs from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Transfection of the AT2 receptor gene downregulated expression of the AT1a receptor in VSMCs from WKY, but did not affect expression of the AT1a receptor in VSMCs from SHR.

Safety and bioactivity of intracoronary delivery of naked plasmid DNA encoding human atrial natriuretic factor.

Aim: To evaluate the safety and bioactivity of catheter-mediated intracoronary gene delivery of naked plasmid DNA encoding human atrial natriuretic factor (hANF).

Methods: hANF gene delivery was performed in 12 canines. For each canine, 4 mg of reconstructed naked plasmid DNA encoding hANF (pCR3*hANF, n=6) or pCR3 (n=6, control) in 2 mL normal saline was injected into left coronary artery via a coronary angiographic catheter.

Angiotensin II type 2 receptor gene transfer downregulates angiotensin II type 1a receptor in vascular smooth muscle cells.

Two distinct subtypes of angiotensin (Ang) II receptors, type 1 (AT(1)) and type 2 (AT(2)), have been identified. Vascular smooth muscle cells (VSMCs) usually express AT(1) receptor. To elucidate the direct effects of the AT(2) receptor on the AT(1) receptor in VSMCs, we transfected AT(2) receptor gene into cultured rat VSMCs.

Novel mechanisms of the antiproliferative effects of amlodipine in vascular smooth muscle cells from spontaneously hypertensive rats.

The calcium channel blocker amlodipine continues to be of interest due to its potential proven ability to hinder the progression of atherosclerosis and reduce the number of clinical ischemic events. Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) are useful in the study of atherosclerosis because they show exaggerated growth with production of angiotensin II (Ang II) by conversion to the synthetic phenotype. To clarify mechanisms of the antiproliferative effects of amlodipine, we evaluated effects of the expression of growth factors, the changes in phenotype, and the proliferation of VSMC from SHR.