669 publications from this institution
Ischemia and reperfusion injury commonly occurs in ischemic heart disease, resulting in apoptotic or necrotic cell death. Apoptotic cell death is highly regulated. Two mechanisms of apoptosis involve the extrinsic death receptor pathway and the intrinsic mitochondrial pathway. Both pathways lead to the activation of effector caspases, resulting in cell death. The mitochondrial pathway plays a key role in initiating apoptosis after ischemia and reperfusion. The phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), and extracellular signal-regulated kinase (ERK) signaling pathways protect the heart against ischemia and reperfusion injury. They inhibit mitochondrial cytochrome c release into the cytosol by regulating the Bcl-2 family proteins and activating the mitoKATP channel, thereby blocking the process of apoptosis.
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates cellular and systemic homeostatic responses (including erythropoiesis, angiogenesis, and glycolysis) to reduced O(2) availability in mammals. Hypoxia induces both the protein expression and transcriptional activity of the HIF-1alpha subunit. However, the molecular mechanisms of sensing and signal transduction by which changes in O(2) concentration result in changes in HIF-1 activity are poorly understood. We report here that the small GTPase Rac1 is activated in response to hypoxia and is required for the induction of HIF-1alpha protein expression and transcriptional activity in hypoxic cells.
Abstract As described in Chapter 3, homeodomain proteins are transcription factors that are characterized by the presence of a 60-amino-acid DNA binding domain. The structure of the homeodomain consists of a flexible amino-terminal arm followed by three a helices (Fig. 9.1) with the second and third helices forming a helix-turn-helix motif that is structurally similar to the DNA binding domain of several prokaryotic transcriptonal repressors (Harrison and Aggarwal, 1990). The carboxyl-terminal third helix of the homeodomain makes direct base contacts with the major groove of the double helix (and is thus known as the recognition helix), the amino-terminal arm makes contact in the minor groove, and there are extensive contacts with the sugar-phosphate backbone (Kissinger et al., 1990; Otting et al., 1990; Wohlberger et al., 1991).
Oxidative phosphorylation enables cells to generate the large amounts of ATP required for development and maintenance of multicellular organisms. However, under conditions of reduced O<sub>2</sub> availability, electron transport becomes less efficient, leading to increased generation of superoxide anions. Hypoxia-inducible factors switch cells from oxidative to glycolytic metabolism, to reduce mitochondrial superoxide generation, and increase the synthesis of NADPH and glutathione, in order to maintain redox homeostasis under hypoxic conditions.
The regulation of tissue perfusion is a major mechanism by which oxygen homeostasis is maintained. Hypoxia‐inducible factor 1 (HIF‐1) is a transcriptional regulator that mediates adaptive responses to reduced partial pressure of O 2 in all metazoan species. In mammals, HIF‐1 promotes angiogenesis, arteriogenesis and vasculogenesis through the production of multiple angiogenic growth factors in ischaemic tissue and by cell‐autonomous effects on endothelial cells and bone marrow‐derived angiogenic cells. Administration of viral vectors encoding constitutively active forms of the HIF‐1α subunit results in increased tissue perfusion in animal models of ischaemic cardiovascular disease.
Twenty-one patients with the diagnosis of mucopolysaccharidosis or mucolipidosis and a history of respiratory complaints or thorough respiratory evaluation were studied retrospectively. Anatomic factors affecting respiratory status included: (i) upper airway narrowing by hypertrophied tongue, tonsils, adenoids, and mucous membranes; (ii) lower airway narrowing by glycosaminoglycan deposition within the tracheobronchial mucosa; (iii) decreased thoracic dimensions due to scoliosis and thoracic hyperkyphosis; and (iv) decreased abdominal dimensions due to lumbar hyperlordosis, gibbus formation and hepatosplenomegaly. Cardiac and neurologic involvement, while present, did not play primary roles in the development of respiratory disease. The functional consequences of these findings included increased risk of developing: (i) respiratory tract infections; (ii) airway compromise during or after anesthesia or sedation; (iii) dyspnea on exertion; (iv) obstructive lung disease; (v) obstructive sleep apnea; and (vi) cor pulmonale. A management approach is presented which can reduce the morbidity and mortality experienced by these patients.
Abstract In this review, the concept of oxygen homeostasis will be presented as an organizing principle for discussion of the phylogeny, ontogeny, physiology, and pathology of blood vessel formation and remodeling, with a focus on molecular mechanisms and potential therapeutic applications. J. Cell. Biochem. 102: 840–847, 2007. © 2007 Wiley‐Liss, Inc.
