Abstract 4147197: Deletion of PKM2 in macrophages fosters stabilization but not regression of atherosclerotic plaques

High-risk human atherosclerotic plaques show a metabolic profile characterized by a high glycolytic flux. Pyruvate kinase M2 is an important regulator of increased glycolytic activity and deletion of PKM2 in macrophages induces a reparatory macrophage phenotype. Given these results, we hypothesized that inhbiting glycolysis in macrophages by deleting PKM2 might induce atherosclerotic regression and present a viable therapeutic target. For this, we employed LDL receptor antisense oligonucleotides in LysM Cre PKM2 flox , allowing us temporal control of the LDL receptor knockdown and thus the induction of atherosclerosis regression by normocholesterolemia after a period of atherosclerotic development. After 16 weeks of Western Diet and ASO treatment, we found no difference in plaque size between PKM2 cKO and littermate PKM2 WT controls. We verified these results in a second centre in Sweden by transplanting either PKM2 cKO or PKM2 WT bone marrow into LDL receptor knockout mice and analysing the plaque area over the entire aortic root after 16 weeks of Western Diet. Despite similar plaque sizes between the two genotypes, we found that plaque collagen content was increased in PKM2 cKO compared to PKM2 WT mice (58±11 vs. 46±9%, p<0.05) whereas CD68 area was significantly decreased (39±10 vs. 23±9%, p<0.05) - mirroring previous results from another group. In line with these results, we found a trend towards more effective efferocytosis in vitro in PKM2 cKO compared to PKM2 WT macrophages. In order to test the effect of PKM2 knockout on plaque regression, we treated PKM2 cKO and PKM2 WT mice with Western Diet and ASOs for 16 weeks, after which we stopped ASO injections and fed them a chow diet for another 4 weeks to induce normocholesterolemia and plaque regression. After 20 weeks of treatment, we did not see a difference in plaque size or markers of plaque stability (lipid/collagen/macrophage content). These findings confirm previous results that PKM2 knockout in macrophages leads to a more stable phenotype in progressing plaques. Nonetheless, after a short period of normocholesterolemia - comparable to initiated statin treatment in patients - this advantage of non-functional PKM2 is lost. We conclude that PKM2 does not appear to be a promising therapeutic target to ameliorate atherosclerosis progression and initiate regression.