PPARgamma Coregulators in Rosiglitazone-Induced Cardiovascular Disease

Summary
Rosiglitazone (Rosi) treats type 2 diabetes (T2D) and effectively lowers blood glucose via the nuclear receptor
PPARγ activation. Rosi has been reduced in use due to it inducing congestive heart failure (CHF). PPARγ is a
ligand-activated transcription factor that is highly expressed in adipose tissues and, to a lesser extent, in cardiac
tissue. It is regulated through various mechanisms, like coregulators that physically interact with PPARγ to
activate or repress its transcriptional activity. Hence, the PPARγ-interactome regulates functions that drive it
toward genes that control specific pathways. My goal for this project is to determine the global genome view of
the heart and adipose tissue during Rosi activation of PPARγ that leads to the deleterious effects associated
with the drug. We will investigate if the PPARγ interactome changes based on diet (high-fat versus chow diets)
and whether this guides the transcription factor to specific PPAR-response elements (PPREs) in gene promoters
inducing specific pathways. These concepts have led to the central hypothesis that chronic high-fat feeding in
the obese causes a change in the PPARγ interactome and pathways controlled by the transcription factor that
leads to cardiac dysfunction. We will measure these in the following aims: Aim 1: We hypothesize that high-fat
(HFD) feeding alters PPARγ-directed pathways in the heart, causing a switch in gene regulatory actions and
cardiac steatosis. Aim 2: We hypothesize that PPARγ activation in adipose tissue of chronically obese mice
activates inflammatory hormones that cause cardiac dysfunction. To measure these, we will use our state-of-
the-art PamGene PamStation to measure the PPARγ coregulator interactome, RNA-sequencing, and PPARγ
chromatin immunoprecipitation (ChIP)-seq in adipose and heart tissues in the mice described above. We expect
to find that chronic high-fat feeding changes the PPARγ coregulator interactome, driving it to pathways that lead
to deleterious outcomes, such as our finding that Serpine1 mRNA (plasminogen activator inhibitor 1, PAI-1
protein) levels were increased in the HFD Rosi, but not in normal chow mice with Rosi treatments. PAI-1 is
involved in cardiovascular disease, but nothing is known about its role in PPARγ-induced CHF. Our studies here
will improve the understanding of PPARγ in cardiac function and possibly provide methods of treating persons
who experience CHF.

Grant Number: 5F31HL175979-02
NIH Institute/Center: NIH
Principal Investigator: EVELYN BATES