Duan Sheng Zhong, Ivashchenko Christine Y, Whitesall Steven E, D'Alecy Louis G, Duquaine Damon C, Brosius Frank C, Gonzalez Frank J, Vinson Charles, Pierre Melissa A, Milstone David S, Mortensen Richard M
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
J Clin Invest. 2007 Mar;117(3):812-22. doi: 10.1172/JCI28859. Epub 2007 Feb 15.
We rescued the embryonic lethality of global PPARgamma knockout by breeding Mox2-Cre (MORE) mice with floxed PPARgamma mice to inactivate PPARgamma in the embryo but not in trophoblasts and created a generalized PPARgamma knockout mouse model, MORE-PPARgamma knockout (MORE-PGKO) mice. PPARgamma inactivation caused severe lipodystrophy and insulin resistance; surprisingly, it also caused hypotension. Paradoxically, PPARgamma agonists had the same effect. We showed that another mouse model of lipodystrophy was hypertensive, ruling out the lipodystrophy as a cause. Further, high salt loading did not correct the hypotension in MORE-PGKO mice. In vitro studies showed that the vasculature from MORE-PGKO mice was more sensitive to endothelial-dependent relaxation caused by muscarinic stimulation, but was not associated with changes in eNOS expression or phosphorylation. In addition, vascular smooth muscle had impaired contraction in response to alpha-adrenergic agents. The renin-angiotensin-aldosterone system was mildly activated, consistent with increased vascular capacitance or decreased volume. These effects are likely mechanisms contributing to the hypotension. Our results demonstrated that PPARgamma is required to maintain normal adiposity and insulin sensitivity in adult mice. Surprisingly, genetic loss of PPARgamma function, like activation by agonists, lowered blood pressure, likely through a mechanism involving increased vascular relaxation.
我们通过将Mox2-Cre（MORE）小鼠与携带floxed PPARγ的小鼠杂交，使胚胎中的PPARγ失活但滋养层细胞中的PPARγ不失活，从而挽救了全身性PPARγ基因敲除导致的胚胎致死性，并创建了一种全身性PPARγ基因敲除小鼠模型，即MORE-PPARγ基因敲除（MORE-PGKO）小鼠。PPARγ失活导致严重的脂肪营养不良和胰岛素抵抗；令人惊讶的是，它还导致低血压。矛盾的是，PPARγ激动剂也有同样的效果。我们发现另一种脂肪营养不良小鼠模型是高血压的，排除了脂肪营养不良是病因。此外，高盐负荷并不能纠正MORE-PGKO小鼠的低血压。体外研究表明，MORE-PGKO小鼠的血管对毒蕈碱刺激引起的内皮依赖性舒张更敏感，但与eNOS表达或磷酸化的变化无关。此外，血管平滑肌对α-肾上腺素能药物的收缩反应受损。肾素-血管紧张素-醛固酮系统轻度激活，与血管容量增加或血容量减少一致。这些效应可能是导致低血压的机制。我们的结果表明，PPARγ是成年小鼠维持正常肥胖和胰岛素敏感性所必需的。令人惊讶的是，PPARγ功能的基因缺失，就像激动剂激活一样，会降低血压，可能是通过一种涉及血管舒张增加的机制。
