Roles for soluble guanylate cyclase and a thiol oxidation-elicited subunit dimerization of protein kinase G in pulmonary artery relaxation to hydrogen peroxide

We have previously provided evidence that hydrogen peroxide (H2O2) stimulates soluble guanylate cyclase (sGC) under conditions where it relaxes isolated endothelium-removed bovine pulmonary arteries (BPAs). Since it was recently reported that H2O2 induces coronary vasorelaxation associated with a nitric oxide/cGMP-independent thiol oxidation/subunit dimerization-elicited activation of protein kinase G (PKG), we investigated whether this mechanism participates in the relaxation of BPAs to H2O2. BPAs precontracted with serotonin (incubated under hypoxia to lower endogenous H2O2) were exposed to increasing concentrations of H2O2. It was observed that 0.1–1 mM H2O2 caused increased PKG dimerization and relaxation. These responses were associated with increased phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at the serine-239 site known to be mediated by PKG. Treatment of BPAs with 1 mM DTT attenuated PKG dimerization, VASP phosphorylation, and relaxation to H2O2. An organoid culture of BPAs for 48 h with 10 μM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a heme oxidant inhibitor of sGC activation, depleted sGC expression by 85%, associated with a 67% attenuation of VASP phosphorylation and 48% inhibition of relaxation elicited by 100 μM H2O2. Thus both a sGC activation/cGMP-dependent and a thiol oxidation subunit dimerization/cGMP-independent activation of PKG appear to contribute to the relaxation of BPAs elicited by H2O2

cGMP-Manufactured Human Induced Pluripotent Stem Cells Are Available for Pre-clinical and Clinical Applications

The discovery of induced pluripotent stem cells (iPSCs) and the concurrent development of protocols for their cell-type-specific differentiation have revolutionized our approach to cell therapy. It has now become critical to address the challenges related to the generation of iPSCs under current good manufacturing practice (cGMP) compliant conditions, including tissue sourcing, manufacturing, testing, and storage. Furthermore, regarding the technical challenges, it is very important to keep the costs of manufacturing and testing reasonable and solve logistic hurdles that permit the global distribution of these products. Here we describe our efforts to develop a process for the manufacturing of iPSC master cell banks (MCBs) under cGMPs and announce the availability of such banks

Living with heart failure: Perspectives of patients from Singapore

Introduction: Heart failure is a progressive and often incurable condition associated with a poor quality of life. The aim of this study was to understand the experiences and preferences regarding care, communication and decision-making among patients living with heart failure in Singapore. Methods: Five focus groups were conducted with 27 patients that had heart failure. The focus groups were audio-recorded and transcribed verbatim. Thematic analysis was used for analyzing transcripts. Results: Six themes representing the experiences of patients with heart failure were identified. These were: 1) physical and psychological symptoms; 2) financial concerns; 3) uncertainty and lack of knowledge about disease; 4) difficulties in navigating the healthcare system; 5) end-of-life care concerns; and 6) fear of burdening family. Conclusion: The study highlights that health care services for patients with heart failure need to address the multifaceted impacts of the disease on patient’s lives. A focus on the provision of comprehensive health care services at the primary care level, training of health care providers in communication skills, involving patients and their families in decision making, and discussions about end-of-life care preferences and goals of care may help to improve care for patients with heart failure