Implications for Growth Differentiation Factor – 11 in Cardiovascular Disease and Metabolic Syndrome

Abstract

While cardiovascular disease is the largest cause of mortality in the United States, its severity is especially pronounced in metabolic syndrome patients. In previous studies, we have shown that coronary collateral growth (CCG) was impaired in Zucker Obese Fatty (ZOF) rats, a rat model of metabolic syndrome while coronary collateral grew extensively in Zucker Lean (ZLN) rats after a 10‐day repetitive ischemia (RI) protocol. To understand the underlying mechanism, we performed microarray and RNA‐seq to profile the gene expression of ischemic heart during coronary collateral growth in ZLN and ZOF rats which underwent the RI protocol. One of the most downregulated genes is Growth Differentiation Factor 11 (Gdf11), which was found to be significantly reduced in ZOF rat hearts compared to ZLN rat hearts and its expression was validated by quantitative RT‐PCR (n = 6). Moreover, Gdf11 mRNA expression is significantly decreased in both diabetic (db/db) and obese (ob/ob) mouse hearts compared to age‐matched wild type mice. To study the role of Gdf11 in vascular dysfunction in metabolic disorder, vascular endothelial cells and induced vascular progenitor cells (iVPCs) were treated with high glucose and high lipid (linoleic, oleic and palmitic acid). Interestingly, Gdf11 expression was decreased significantly under these treatments. Furthermore, we study the role of Gdf11 in the cardiovascular development and diseases using Gdf11 knockout mice with a LacZ gene knock in, which could track the gene expression of Gdf11 by LacZ staining. Whole‐mount of X‐gal staining showed that that Gdf11 is mostly expressed in the vasculature of the heart. Histological analyses confirmed that Gdf11 is expressed in blood vessels throughout the myocardium. These preliminary data suggested that 1) Gdf11 is downregulated in the heart of rodent models of metabolic syndrome and it might contribute to impaired coronary collateral growth in ZOF rats; 2) high glucose or high fatty acid affects the Gdf11 expression; 3) genetic studies show that Gdf11 is highly expressed in myocardial blood vessels, which suggests the role of Gdf11 in vascular growth. Gdf11 is controversial in its function in aging. However, our study is more focused on the function of Gdf11 in cardiovascular development and diseases. Using a Gdf11 knockout model will enable us to interrogate this controversy.Support or Funding InformationThe research is funded by National Institutes of Health grant 2R01HL103227‐05(YZ, LY), 1R01HL135110‐01 (WMC, LY), 1 R01 HL137008‐01A1 (LY), 1R15HL115540‐01 (LY) and 14BGIA18770028 from American Heart Association.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.