Exacerbated vein graft arteriosclerosis in protein kinase Cδ–null mice
Michael Leitges, … , Yanhua Hu, Qingbo Xu
Michael Leitges, … , Yanhua Hu, Qingbo Xu
Published November 15, 2001
Citation Information: J Clin Invest. 2001;108(10):1505-1512. https://doi.org/10.1172/JCI12902.
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Article

Exacerbated vein graft arteriosclerosis in protein kinase Cδ–null mice

Abstract

Smooth muscle cell (SMC) accumulation is a key event in the development of atherosclerosis, including vein bypass graft arteriosclerosis. Because members of the protein kinase C (PKC) family signal cells to undergo proliferation, differentiation, or apoptosis, we generated PKCδ knockout mice and performed vein bypass grafts on these animals. PKCδ–/– mice developed normally and were fertile. Vein segments from PKCδ–/– mice isografted to carotid arteries of recipient mice of either genotype led to a more severe arteriosclerosis than was seen with PKCδ+/+ vein grafts. Arteriosclerotic lesions in PKCδ–/– mice showed a significantly higher number of SMCs than were found in wild-type animals; this was correlated with decreased SMC death in lesions of PKCδ–/– mice. SMCs derived from PKCδ–/– aortae were resistant to cell death induced by any of several stimuli, but they were similar to wild-type SMCs with respect to mitogen-stimulated cell proliferation in vitro. Furthermore, pro-apoptotic treatments led to diminished caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and cytochrome c release in PKCδ–/– relative to wild-type SMCs, suggesting that their apoptotic resistance involves the loss of free radical generation and mitochondrial dysfunction in response to stress stimuli. Our data indicate that PKCδ maintains SMC homeostasis and that its function in the vessel wall per se is crucial in the development of vein graft arteriosclerosis.

Authors

Michael Leitges, Manuel Mayr, Ursula Braun, Ursula Mayr, Chaohong Li, Gerald Pfister, Nassim Ghaffari-Tabrizi, Gottfried Baier, Yanhua Hu, Qingbo Xu

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Figure 1

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Targeted mutation of the PKCδ locus in mice (a) Restriction map of the P...
Targeted mutation of the PKCδ locus in mice (a) Restriction map of the PKCδ locus (wt). The targeting vector was integrated into the endogenous locus by homologous recombination and gave rise to the mutant PKCδ LacZ locus. B, BamHI; E, EcoRI; H, HindIII; F, FspI. (b) Southern blot analysis of a litter derived from a heterozygote intercross. Genomic EcoRI fragments detected with a 5′-probe indicating wild-type (wt) and mutant (mt) alleles. The homozygote animal is represented in lane 1; heterozygote animals are represented in lanes 2 and 4; lane 3 is representative for wild-type animals. (c) Western blot analysis of protein extracts from homozygote and wild-type mice showing undetectable PKCδ proteins of tissues from PKCδ knockout mice.