SMC-specific PI3Kα ablation in Apoe-/- mice exacerbated atherosclerosis, increasing whole aorta lesion area compared with controls (5.9% vs 3.4%, P<0.0001) and reducing plaque stability.
Does SMC-specific PI3Kα ablation exacerbate atherosclerosis progression and plaque instability in Apoe-/- mice?
SMC-specific PI3Kα ablation exacerbates atherosclerosis and plaque instability in Apoe-/- mice, suggesting that PI3Kα in smooth muscle cells protects against atherosclerosis progression.
Absolute Event Rate: 5.9% vs 3.4%
p-value: p=<0.0001
Abstract Background Atherosclerosis is a chronic inflammatory disease of the arterial wall caused by intimal lipoprotein retention, maladaptive inflammatory responses and vascular remodelling processes. Vascular smooth muscle cells (SMCs) play a crucial role in atherosclerotic plaque development and progression by exerting both important atheroprotective and proatherogenic functions including formation and stabilisation of the fibrous plaque cap as well as transition into foam cells. Recent studies suggest an important role of pleiotropic growth factors and cytokines such as the platelet-derived growth factor (PDGF) in the regulation of these processes. Previous studies from our lab have shown that the class I phosphatidylinositol 3'-kinase isoform α (PI3Kα) is a key signalling enzyme downstream of PDGF receptors, critically controlling the proliferation, survival and migration of SMCs in vascular remodelling processes and pulmonary hypertension. Thus, the aim of our study was to elucidate the unknown role of PI3Kα in SMCs during atherosclerosis. Methods and Results SMC-specific PI3Kα-deficient Apoe-/- (Apoe-/-SMC-PI3Kα-/-) mice and Apoe-/- controls were fed a Western diet for 12 weeks. Unexpectedly, SMC-specific PI3Kα ablation yielded a considerable exacerbation of atherosclerosis. The atherosclerotic lesion area in the whole aorta of Apoe-/-SMC-PI3Kα-/- mice was increased compared with Apoe-/- controls (5.9% versus 3.4%, P0.0001, N = 21-23). Accordingly, atherosclerotic lesions in the aortic roots of Apoe-/-SMC-PI3Kα-/- mice were enlarged (8.8% versus 6.4%, P0.05, N = 17 -19), though these mice displayed similar body weight and serum lipid levels as Apoe-/- controls. Further analyses revealed that despite exacerbated atherosclerosis, the relative plaque proportion of Mac-2+ macrophages in Apoe-/-SMC-PI3Kα-/- mice remained similar to Apoe-/- controls. However, SMC-specific PI3Kα deficiency resulted in reduced indices of plaque stability including reduced collagen content (11.0% versus 29.5%, P0.0001, N = 17-18) as shown by Masson’s trichrome staining. Importantly, SMC-specific PI3Kα ablation exacerbated aortic inflammation already in SMC-PI3Kα-/- mice at baseline as evidenced by increased mRNA expression of the macrophage marker Cd68, proatherogenic Ccl2 chemokine and Klf4 transcription factor compared with controls. Thus, SMC-specific PI3Kα ablation causes enhanced aortic inflammation, atherosclerosis and plaque instability through unknown mechanisms which may include arterial wall properties influencing atherosclerosis susceptibility. Conclusions Although further investigations of PI3Kα-dependent mechanisms in SMCs during atherogenesis remain to be elucidated, our results indicate that PI3Kα is a central regulator of SMC biology and thereby protect against atherosclerosis progression and plaque instability. Thus, fine-tuning the PI3Kα signalling pathway in SMCs may represent a future therapeutic or preventive strategy.
Zierden et al. (Sat,) conducted a other in Atherosclerosis. SMC-specific PI3Kα ablation vs. Apoe-/- controls was evaluated on Atherosclerotic lesion area in the whole aorta (p=<0.0001). SMC-specific PI3Kα ablation in Apoe-/- mice exacerbated atherosclerosis, increasing whole aorta lesion area compared with controls (5.9% vs 3.4%, P<0.0001) and reducing plaque stability.