?s abstract) In an era of relatively easy control of LDL, other aspects of dyslipidemia and allied metabolic abnormalities emerge as an increasingly challenging and prevalent clinical problem. Insulin resistance, adiposity, hypertension, hypertriglyceridemia, and low levels of high density lipoprotein (HDL) constitute a constellation of risk factors know as the """"""""metabolic syndrome."""""""" The mechanisms which link these seemingly diverse findings and the pathogenesis of vascular disease remain relatively unexplored. In addition, an important clinical need for improved therapy of the """"""""metabolic syndrome"""""""" exists. Even strict glycemic control with insulin may not forestall the ravages of the metabolic syndrome on the macrovasculature in insulin-resistant patients. An improved understanding of the pathways by which elements of the metabolic syndrome intersect with the pathogenesis of arterial diseases should promote the adoption of rational therapeutic regimens. Project 3, led by Dr. Plutzky, will explore the molecular mechanisms of the metabolic syndrome using an innovative unifying approach. Dr. Plutzky?s project will focus on the transcriptional control system infelicitously and misleadingly call the """"""""peroxisomal proliferation activating receptor"""""""" (PPAR) family. In work published in 1998 from several laboratories including our own, the significance of the PPAR transcriptional control has expanded beyond adipose tissue and hepatocytes to macrophages and vascular smooth muscle cells as well. Several laboratories have documented PPARy-dependent inhibition of inflammatory gene expression in macrophages. Others have found that PPARalpha stimulation can inhibit interleukin-1 induced interleukin-6 expression by vascular smooth muscle cells, a function first described by Dr. Libby?s laboratory nearly a decade ago. Dr. Plutzky?s preliminary data indicate that PPARalpha activation can inhibit cytokine-induced inflammatory activation of human endothelial cells. This burgeoning of recent findings provide an intriguing and novel link between adipose tissue and hepatic lipid metabolism and anti-inflammatory functions of atheroma-associated cells. Interestingly, very recent work has established that components of oxidized low density lipoprotein can activate PPARs, increasing expression by macrophages of the scavenger receptor CD36, and potentially promoting foam cell formation. Thus PPAR activation may have a duality of actions that promote or inhibit different aspects of arterial dysfunction. This confusing picture in vitro illustrates the essential value of the integrative in vivo experiments in genetically altered mice proposed by Dr. Plutzky. Enticingly, agents now used to treat diabetic dyslipidemia and hyperglycemia can activate PPARs. For example, fibric acid derivatives activate PPARalpha. Thiazolidinediones, recently introduced for treatment of diabetes, can activate PPARy. These therapeutic agents, increasingly applied in clinical practice, may have mechanisms of action directly affecting the artery wall independent on hypoglycemic and/or anti-hyperlipidemic actions hitherto unsuspected. Dr. Plutzky?s project will pursue the study of pro- and anti-inflammatory effects of PPAR stimulation and test the hypothesis that PPARs participate in regulation of genes not currently recognized as PPAR targets of potential importance in arterial dysfunction. Specifically, this study will address the molecular mechanisms by which PPAR-alpha stimulation inhibits the transcription of vascular cell adhesion molecule-1 (VCAM-1), and how PPAR-gamma stimulation modulates the transcription of plasminogen activator inhibitor-1 (PAI-1) in endothelial cells. Dr. Plutzky?s studies will also test the hypothesis that PPAR-alpha plays a role in atherogenesis and vascular cell activation using genetically-modified mice. Dr. Plutzky?s project will link to Dr. Creager?s exploration of arterial dysfunction in diabetes, as Thiazolidinediones to be studied in human subjects in Project 5 have as their molecular mechanism activation of PPARy. Dr. Plutzky?s project will interface with the molecular of Dr. Liao in Project 2 as described above. Dr. Plutzky?s project will continue to benefit from Dr. Libby?s long standing interest in cytokine biology and the link between inflammation and lipid metabolism. The pilot data generated for Project 3 utilized specimens and expertise available in the Vascular pathology Core and will continue to do so. The analysis of the phenotype of genetically modified mice will also depend on this Core.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Steinhorn, Benjamin; Sorrentino, Andrea; Badole, Sachin et al. (2018) Chemogenetic generation of hydrogen peroxide in the heart induces severe cardiac dysfunction. Nat Commun 9:4044
Brown, Jonathan D; Feldman, Zachary B; Doherty, Sean P et al. (2018) BET bromodomain proteins regulate enhancer function during adipogenesis. Proc Natl Acad Sci U S A 115:2144-2149
Samokhin, Andriy O; Stephens, Thomas; Wertheim, Bradley M et al. (2018) NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension. Sci Transl Med 10:
Pang, Paul; Abbott, Molly; Abdi, Malyun et al. (2018) Pre-clinical model of severe glutathione peroxidase-3 deficiency and chronic kidney disease results in coronary artery thrombosis and depressed left ventricular function. Nephrol Dial Transplant 33:923-934
Steinhorn, Benjamin; Sartoretto, Juliano L; Sorrentino, Andrea et al. (2017) Insulin-dependent metabolic and inotropic responses in the heart are modulated by hydrogen peroxide from NADPH-oxidase isoforms NOX2 and NOX4. Free Radic Biol Med 113:16-25
Handy, Diane E; Loscalzo, Joseph (2017) Responses to reductive stress in the cardiovascular system. Free Radic Biol Med 109:114-124
Liu, Cong-Lin; Wang, Yi; Liao, Mengyang et al. (2016) Allergic Lung Inflammation Aggravates Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice. Arterioscler Thromb Vasc Biol 36:69-77
Machlus, Kellie R; Wu, Stephen K; Stumpo, Deborah J et al. (2016) Synthesis and dephosphorylation of MARCKS in the late stages of megakaryocyte maturation drive proplatelet formation. Blood 127:1468-80
Liu, Cong-Lin; Wemmelund, Holger; Wang, Yi et al. (2016) Asthma Associates With Human Abdominal Aortic Aneurysm and Rupture. Arterioscler Thromb Vasc Biol 36:570-8
Garmaroudi, Farshid S; Handy, Diane E; Liu, Yang-Yu et al. (2016) Systems Pharmacology and Rational Polypharmacy: Nitric Oxide-Cyclic GMP Signaling Pathway as an Illustrative Example and Derivation of the General Case. PLoS Comput Biol 12:e1004822

Showing the most recent 10 out of 266 publications