Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability to sense and respond to changes in oxygen availability is critical for many developmental, physiological, and pathological processes, including angiogenesis, control of blood pressure, and cerebral and myocardial ischemia. Hypoxia-inducible factor-1alpha (HIF-1alpha) is a basic-helix-loop-helix (bHLH)containing member of the PER-ARNT-SIM (PAS) family of transcription factors that plays a central role in the response to hypoxia. HIF-1alpha, and its relatives HIF-2alpha/endothelial PAS domain protein (EPAS) and HIF-3alpha, are induced in response to hypoxia and serve to coordinately activate the expression of target genes whose products facilitate cell survival under conditions of oxygen deprivation. When cells are exposed to chronic hypoxia, the protective response can fail, resulting in apoptosis. This study shows that transcription of the gene encoding Nip3, a proapoptotic member of the Bcl-2 family of cell death factors, is strongly induced in response to hypoxia. The Nip3 promoter contains a functional HIF-1-responsive element (HRE) and is potently activated by both hypoxia and forced expression of HIF-1alpha. Exposure of cultured cells to chronic hypoxia results in the accumulation of a protein recognized by antibodies raised against Nip3. This study demonstrates a direct link between HIF-1alpha and a proapoptotic member of the Bcl-2 family and offers a reasonable physiological function for members of the Bcl-2 subfamily, including Nip3 and its close relative Nix. These observations indicate that Nip3 may play a dedicated role in the pathological progression of hypoxia-mediated apoptosis, as observed after ischemic injury.
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PMID:Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. 1092 63

Clinical heart failure results from the cumulative loss of functioning myocardium from any cause. At the cellular level, cardiac myocytes die from three causes, individually or in combination: Necrosis occurs when external conditions are not sufficient to sustain minimal cellular functions, as with ischemia, and there is a general and unorganized breakdown of cell organelles, engendering an inflammatory response that may have harmful collateral tissue effects. Apoptosis, or cell suicide, occurs when specific external or internal conditions provoke a highly structured sequence of events to shut down cellular functions and remove the cell, with minimal consequences to surrounding tissue. Autophagy is a normal response to cell starvation that is induced under conditions of chronic metabolic or other stress. Current therapeutics, such as early myocardial revascularization after myocardial infarction, are focused exclusively upon minimizing cardiac myocyte necrosis and may even contribute to secondary apoptosis and autophagy. This review explores possible approaches to bring cardiac myocytes that are destined to die, back to life, i.e., cellular resuscitation. Two pro-apoptotic proteins in particular, Bnip3 and Nix, are transcriptionally upregulated specifically in response to myocardial ischemia and pathological hypertrophy and have been examined as therapeutic targets. In Bnip3 and Nix genetic mouse models, prevention of cardiac myocyte apoptosis in ischemic and hemodynamically overloaded hearts salvaged myocardium, minimized late ventricular remodeling, and enhanced ventricular performance. Cardiomyocyte resuscitation by preventing programmed cell death shows promise as an additive approach to minimizing necrosis for long-term prevention of heart failure.
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PMID:The rationale for cardiomyocyte resuscitation in myocardial salvage. 1856 79

Myocardin is a transcriptional co-activator required for cardiovascular development, but also promotes cardiomyocyte survival through an unclear molecular mechanism. Mitochondrial permeability transition is implicated in necrosis, while pore closure is required for mitochondrial maturation during cardiac development. We show that loss of myocardin function leads to subendocardial necrosis at E9.5, concurrent with elevated expression of the death gene Nix. Mechanistically, we demonstrate that myocardin knockdown reduces microRNA-133a levels to allow Nix accumulation, leading to mitochondrial permeability transition, reduced mitochondrial respiration, and necrosis. Myocardin knockdown elicits calcium release from the endo/sarcoplasmic reticulum with mitochondrial calcium accumulation, while restoration of microRNA-133a function, or knockdown of Nix rescues calcium perturbations. We observed reduced myocardin and elevated Nix expression within the infarct border-zone following coronary ligation. These findings identify a myocardin-regulated pathway that maintains calcium homeostasis and mitochondrial function during development, and is attenuated during ischemic heart disease. Given the diverse role of Nix and microRNA-133a, these findings may have broader implications to metabolic disease and cancer.
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PMID:Myocardin regulates mitochondrial calcium homeostasis and prevents permeability transition. 3164 Dec 43