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Mclk1+/- mice are not resistant to the development of atherosclerosis.

Hughes BG, Hekimi S - Lipids Health Dis (2009)

Bottom Line: The prolonged survival implies a decreased mortality from age-dependent lethal pathologies.Furthermore, the absence of ApoE suppressed the lifespan-promoting effects of Mclk1 heterozygosity.Moreover, in the presence of hyperlipidemia and chronic inflammation, Mclk1 heterozygosity is incapable of extending lifespan.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, McGill University, Montreal H3A 1B1, Canada. bryan.hughes@mail.mcgill.ca

ABSTRACT

Background: Mice with a single copy of Mclk1 (a.k.a. Coq7), a gene that encodes a mitochondrial enzyme required for the biosynthesis of ubiquinone and other functions, live longer than wild-type mice. The prolonged survival implies a decreased mortality from age-dependent lethal pathologies. Atherosclerosis is one of the main age-dependent pathologies in humans and can be modeled in mice that lack Apolipoprotein E (ApoE-/-) or mice that lack the Low Density Lipoprotein Receptor (LDLr-/-) in addition to being fed an atherosclerosis-inducing diet. We sought to determine if Mclk1 heterozygosity protects against atherosclerosis and dyslipidemia in these models.

Results: We found that Mclk1 heterozygosity did not protect against dyslipidemia, oxidative stress, or atherosclerosis in young (6 or 10 months) or older (18 months) mice. Furthermore, the absence of ApoE suppressed the lifespan-promoting effects of Mclk1 heterozygosity.

Conclusion: These findings indicate that although Mclk1 heterozygosity can extend lifespan of mice, it does not necessarily protect against atherosclerosis. Moreover, in the presence of hyperlipidemia and chronic inflammation, Mclk1 heterozygosity is incapable of extending lifespan.

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Related in: MedlinePlus

Heterozygosity for Mclk1 does not prevent atherosclerosis in the LDLr-/- disease model. Atherosclerotic lesions that stain with the lipid-sensitive dye Oil Red O were quantified on the inner surface of the aorta in LDLr-/- mice at (A) 6 months of age, with three backcrosses into C57BL/6J and (B) 10 months of age with six backcrosses into C57BL/6J. F and M labels stand for females and males, respectively. The +/+ and +/- labels stand for the Mclk1+/+ and Mclk1+/- genotypes, respectively.
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Figure 1: Heterozygosity for Mclk1 does not prevent atherosclerosis in the LDLr-/- disease model. Atherosclerotic lesions that stain with the lipid-sensitive dye Oil Red O were quantified on the inner surface of the aorta in LDLr-/- mice at (A) 6 months of age, with three backcrosses into C57BL/6J and (B) 10 months of age with six backcrosses into C57BL/6J. F and M labels stand for females and males, respectively. The +/+ and +/- labels stand for the Mclk1+/+ and Mclk1+/- genotypes, respectively.

Mentions: To determine if Mclk1 heterozygosity protected against atherosclerosis, Mclk1+/- mice were crossed into atherosclerosis-sensitive ApoE-/- and LDLr-/- backgrounds. The proportion of the inner aortic surface occupied by atherosclerotic lesions was then quantified. Atherosclerosis in both the ApoE-/- and LDLr-/- models of the disease was not inhibited by Mclk1 heterozygosity (Figures 1 and 2). In one condition (ApoE-/- mice sacrificed at 10 months of age), Mclk1+/- females had increased atherosclerosis (6.8 vs. 10 percent of aortic surface area, p = 0.0146). In the same experiment, there was a 37 percent decrease in atherosclerosis in Mclk1+/- males that was not statistically significant (p = 0.21). As the mice in this cohort had only been backcrossed for four generations, it is possible that high variability due to genetic heterogeneity could have been masking an effect of Mclk1 heterozygosity in males. We therefore repeated this study in a second group of ApoE-/- mice that had been backcrossed ten generations onto the C57BL/6J background. In this second cohort of mice, there was no effect of Mclk1 heterozygosity in either gender.


Mclk1+/- mice are not resistant to the development of atherosclerosis.

Hughes BG, Hekimi S - Lipids Health Dis (2009)

Heterozygosity for Mclk1 does not prevent atherosclerosis in the LDLr-/- disease model. Atherosclerotic lesions that stain with the lipid-sensitive dye Oil Red O were quantified on the inner surface of the aorta in LDLr-/- mice at (A) 6 months of age, with three backcrosses into C57BL/6J and (B) 10 months of age with six backcrosses into C57BL/6J. F and M labels stand for females and males, respectively. The +/+ and +/- labels stand for the Mclk1+/+ and Mclk1+/- genotypes, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2683836&req=5

Figure 1: Heterozygosity for Mclk1 does not prevent atherosclerosis in the LDLr-/- disease model. Atherosclerotic lesions that stain with the lipid-sensitive dye Oil Red O were quantified on the inner surface of the aorta in LDLr-/- mice at (A) 6 months of age, with three backcrosses into C57BL/6J and (B) 10 months of age with six backcrosses into C57BL/6J. F and M labels stand for females and males, respectively. The +/+ and +/- labels stand for the Mclk1+/+ and Mclk1+/- genotypes, respectively.
Mentions: To determine if Mclk1 heterozygosity protected against atherosclerosis, Mclk1+/- mice were crossed into atherosclerosis-sensitive ApoE-/- and LDLr-/- backgrounds. The proportion of the inner aortic surface occupied by atherosclerotic lesions was then quantified. Atherosclerosis in both the ApoE-/- and LDLr-/- models of the disease was not inhibited by Mclk1 heterozygosity (Figures 1 and 2). In one condition (ApoE-/- mice sacrificed at 10 months of age), Mclk1+/- females had increased atherosclerosis (6.8 vs. 10 percent of aortic surface area, p = 0.0146). In the same experiment, there was a 37 percent decrease in atherosclerosis in Mclk1+/- males that was not statistically significant (p = 0.21). As the mice in this cohort had only been backcrossed for four generations, it is possible that high variability due to genetic heterogeneity could have been masking an effect of Mclk1 heterozygosity in males. We therefore repeated this study in a second group of ApoE-/- mice that had been backcrossed ten generations onto the C57BL/6J background. In this second cohort of mice, there was no effect of Mclk1 heterozygosity in either gender.

Bottom Line: The prolonged survival implies a decreased mortality from age-dependent lethal pathologies.Furthermore, the absence of ApoE suppressed the lifespan-promoting effects of Mclk1 heterozygosity.Moreover, in the presence of hyperlipidemia and chronic inflammation, Mclk1 heterozygosity is incapable of extending lifespan.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, McGill University, Montreal H3A 1B1, Canada. bryan.hughes@mail.mcgill.ca

ABSTRACT

Background: Mice with a single copy of Mclk1 (a.k.a. Coq7), a gene that encodes a mitochondrial enzyme required for the biosynthesis of ubiquinone and other functions, live longer than wild-type mice. The prolonged survival implies a decreased mortality from age-dependent lethal pathologies. Atherosclerosis is one of the main age-dependent pathologies in humans and can be modeled in mice that lack Apolipoprotein E (ApoE-/-) or mice that lack the Low Density Lipoprotein Receptor (LDLr-/-) in addition to being fed an atherosclerosis-inducing diet. We sought to determine if Mclk1 heterozygosity protects against atherosclerosis and dyslipidemia in these models.

Results: We found that Mclk1 heterozygosity did not protect against dyslipidemia, oxidative stress, or atherosclerosis in young (6 or 10 months) or older (18 months) mice. Furthermore, the absence of ApoE suppressed the lifespan-promoting effects of Mclk1 heterozygosity.

Conclusion: These findings indicate that although Mclk1 heterozygosity can extend lifespan of mice, it does not necessarily protect against atherosclerosis. Moreover, in the presence of hyperlipidemia and chronic inflammation, Mclk1 heterozygosity is incapable of extending lifespan.

Show MeSH
Related in: MedlinePlus