Endothelial dysfunction in adipose triglyceride lipase deficiency

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• 作者：Astrid Schrammel^a ; ^{astrid.schrammel-gorren@uni-graz.at" class="auth_mail} ; Marion Mussbacher^a ; ^{marion.mussbacher@uni-graz.at" class="auth_mail} ; Gerald Wö ; lkart^a ; ^{gerald.woelkart@uni-graz.at" class="auth_mail} ; Heike Stessel^a ; ^{heike.stessel@uni-graz.at" class="auth_mail} ; Karoline Pail^a ; ^{karoline.pail@uni-graz.at" class="auth_mail} ; Sarah Winkler^a ; ^{sarah.winkler@uni-graz.at" class="auth_mail} ; Martina Schweiger^b ; ^{tina.schweiger@uni-graz.at" class="auth_mail} ; Guenter Haemmerle^b ; ^{guenter.haemmerle@uni-graz.at" class="auth_mail} ; Wael Al Zoughbi^c ; ^{wael.alzoughbi@stud.medunigraz.at" class="auth_mail} ; Gerald Hö ; fler^c ; ^{gerald.hoefler@medunigraz.at" class="auth_mail} ; Alois Lametschwandtner^d ; ^{Alois.Lametschwandtner@sbg.ac.at" class="auth_mail} ; Rudolf Zechner^b ; ^{rudolf.zechner@uni-graz.at" class="auth_mail} ; Bernd Mayer^a ; ^{mayer@uni-graz.at" class="auth_mail}
• 关键词：ACh ; acetylcholine ; ATGL ; adipose triglyceride lipase ; AKO ; adipose triglyceride lipase knockout ; BIP ; binding immunoglobulin protein ; BK ; bradykinin ; BSA ; bovine serum albumin ; CD31 ; cluster of differentiation 31 ; CL ; chemiluminescence ; CPP ; coronary perfusion pressure ; DEA/NO ; 2 ; 2-diethyl-1-nitroso-oxyhydrazine ; DMEM ; Dulbecco's Modified Eagle Medium ; EDTA ; ethylenediaminetetraacetic acid ; eNOS ; endothelial nitric oxide synthase ; GAPDH ; glyceraldehyde-3-phosphate dehydrogenase ; H&E ; hematoxyli
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：June, 2014
• 年：2014
• 卷：1841
• 期：6
• 页码：906-917
• 全文大小：1463 K

文摘

Systemic knockout of adipose triglyceride lipase (ATGL), the pivotal enzyme of triglyceride lipolysis, results in a murine phenotype that is characterized by progredient cardiac steatosis and severe heart failure. Since cardiac and vascular dysfunction have been closely related in numerous studies we investigated endothelium-dependent and -independent vessel function of ATGL knockout mice. Aortic relaxation studies and Langendorff perfusion experiments of isolated hearts showed that ATGL knockout mice suffer from pronounced micro- and macrovascular endothelial dysfunction. Experiments with agonists directly targeting vascular smooth muscle cells revealed the functional integrity of the smooth muscle cell layer. Loss of vascular reactivity was restored ~ 50% upon treatment of ATGL knockout mice with the PPAR伪 agonist Wy14,643, indicating that this phenomenon is partly a consequence of impaired cardiac contractility. Biochemical analysis revealed that aortic endothelial NO synthase expression and activity were significantly reduced in ATGL deficiency. Enzyme activity was fully restored in ATGL mice treated with the PPAR伪 agonist. Biochemical analysis of perivascular adipose tissue demonstrated that ATGL knockout mice suffer from perivascular inflammatory oxidative stress which occurs independent of cardiac dysfunction and might contribute to vascular defects. Our results reveal a hitherto unrecognized link between disturbed lipid metabolism, obesity and cardiovascular disease.