Key result
VSMC PPARγ deletion exaggerates ET-1-induced vascular injury, oxidative stress, and inflammation in mice.
Why the study?
Does VSMC Pparγ inactivation exaggerate ET-1-induced vascular injury in mice?
Does VSMC Pparγ inactivation exaggerate ET-1-induced vascular injury in mice?
VSMC PPARγ protects against ET-1-induced vascular damage, suggesting its activation could be beneficial in hypertension-related vascular injury.
Hypothesis-generating for VSMC PPARγ protection in ET-1 vascular injury; leaves open therapeutic relevance in human hypertension.
AIMS: Peroxisome proliferator-activated receptor γ (PPARγ) agonists reduce blood pressure and vascular injury in hypertensive rodents. Pparγ inactivation in vascular smooth muscle cells (VSMC) enhances vascular injury. Transgenic mice overexpressing endothelin (ET)-1 selectively in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of the Pparγ gene in VSMC (smPparγ-/-) would exaggerate ET-1-induced vascular injury. METHODS AND RESULTS: eET-1, smPparγ-/- and eET-1/smPparγ-/- mice were treated with tamoxifen for 5 days and studied 4 weeks later. SBP was higher in eET-1 and unaffected by smPparγ inactivation. Mesenteric artery vasodilatory responses to acetylcholine were impaired only in smPparγ-/-. N(omega)-Nitro-L-arginine methyl ester abrogated relaxation responses, and the Ednra/Ednrb mRNA ratio was decreased in eET-1/smPparγ-/-, which could indicate that nitric oxide production was enhanced by ET-1 stimulation of endothelin type B receptors. Mesenteric artery media/lumen was greater only in eET-1/smPparγ-/-. Mesenteric artery reactive oxygen species increased in smPparγ and were further enhanced in eET-1/smPparγ-/-. Perivascular fat monocyte/macrophage infiltration was higher in eET-1 and smPparγ and increased further in eET-1/smPparγ-/-. Spleen CD11b+ cells were increased in smPparγ-/- and further enhanced in eET-1/smPparγ-/-, whereas Ly-6C(hi) monocytes increased in eET-1 and smPparγ-/- but not in eET-1/smPparγ-/-. Spleen T regulatory lymphocytes increased in smPparγ and decreased in eET-1, and decreased further in eET-1/smPparγ-/-. CONCLUSION: VSMC Pparγ inactivation exaggerates ET-1-induced vascular injury, supporting a protective role for PPARγ in hypertension through modulation of pro-oxidant and proinflammatory pathways. Paradoxically, ET-1 overexpression preserved endothelial function in smPparγ-/- mice, presumably by enhancing nitric oxide through stimulation of endothelin type B receptors.
No takes yet. Share an insight, caveat, or question.
Idris-Khodja et al. (2017) studied Endothelin-1-induced vascular injury. VSMC Pparγ inactivation vs. Control mice was evaluated on Vascular injury, oxidative stress, and inflammation. VSMC Pparγ inactivation exaggerates ET-1-induced vascular injury, oxidative stress, and inflammation, supporting a protective role for PPARγ in hypertension.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: