Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The harlequin (hq)/Big Blue mouse is a novel model of premature ageing distinguished by a patchy coat, early-onset neurodegeneration, stress-induced heart disease and a mutation detection assay applicable to individual tissues. The hq mutation causes down-regulation of apoptosis-inducing factor and an elevation of reactive oxygen species (ROS). Neural tissues have elevated mutant frequency and early-onset degeneration. This is the first examination of mutations and histology in the skin of hq disease mice. The frequency and pattern of cII mutations in skin from adult hq disease and wild-type (WT) mice 15 days after a single intraperitoneal (i.p.) injection of paraquat (PQ; 10 mg/kg) or vehicle control (VC) were determined to assess spontaneous mutagenesis and sensitivity to an exogenous ROS-inducing mutagen. Skin of hq disease mice shows elevated levels of ROS (P < 0.001) and reduced numbers of hair follicles and associated epidermal cells (P < 0.001) compared to WT control. Acute PQ exposure did not produce detectable skin histopathology. Spontaneous and PQ-induced mutation frequency is elevated in hq skin (P = 0.03 and P = 0.01, respectively) compared to VC-treated WT mice. Despite elevated mutation frequency, mutation patterns were unaltered. Acute PQ exposure resulted in a 1.6-fold increase in mutation frequency in WT mice compared to the level of spontaneous mutations but no significant impact on mutation frequency in hq disease mice. Increased mutation frequency in skin of hq disease mice may be relevant to mechanisms underlying the patchy coat and useful as a biomarker in tests of antioxidant efficacy in preventing the hq disease phenotype. Unaltered mutation patterns with hq disease are consistent with the multiple mutation types associated with ROS. Acute PQ exposure had only subtle effects in WT mice and reduced mitochondrial complex I activity and elevated antioxidant enzyme activity in hq disease mice may lead to PQ resistance.
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PMID:Spontaneous mutation frequency is elevated in skin of harlequin (hq)/Big Blue mice. 2008 2

Age is a major risk factor for heart disease, and cardiac aging is characterized by elevated mitochondrial reactive oxygen species (ROS) with compromised mitochondrial and nuclear DNA integrity. To assess links between increased ROS levels and mutations, we examined in situ levels of ROS and cII mutation frequency, pattern and spectrum in the heart of harlequin (hq)/Big Blue mice. The hq mouse is a model of premature aging with mitochondrial dysfunction and increased risk of oxidative stress-induced heart disease with the means for in vivo mutation detection. The hq mutation produces a significant downregulation in the X-linked apoptosis-inducing factor gene (Aif) impairing both the antioxidant and oxidative phosphorylation functions of AIF. Brain and skin of hq disease mice have elevated frequencies of point mutations in nuclear DNA and histopathology characterized by cell loss. Reports of associated elevations in ROS in brain and skin have mixed results. Herein, heart in situ ROS levels were elevated in hq disease compared to AIF-proficient mice (p<0.0001) yet, mutation frequency and pattern were similar in hq disease, hq carrier and AIF-proficient mice. Heart cII mutations were also assessed 15 days following an acute exposure to an exogenous ROS inducer (10 mg paraquat/kg). Acute paraquat exposure with a short mutant manifestation period was insufficient to elevate mutation frequency or alter mutation pattern in the post-mitotic heart tissue of AIF-proficient mice. Paraquat induction of ROS requires mitochondrial complex I and thus is likely compromised in hq mice. Results of this preliminary survey and the context of recent literature suggest that determining causal links between AIF deficiency and the premature aging phenotypes of specific tissues is better addressed with assay of mitochondrial ROS and large-scale changes in mitochondrial DNA in specific cell types.
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PMID:Heart tissue of harlequin (hq)/Big Blue mice has elevated reactive oxygen species without significant impact on the frequency and nature of point mutations in nuclear DNA. 2054 63