Research

Brian Rodrigues

“Research at the Rodrigues Lab isn’t just about the heart. In our process, we have heart.”

Research Projects

  • An early change in cardiac metabolism is considered a major culprit for diabetic cardiomyopathy (DCM). The earliest metabolic change occurring in the diabetic heart is reduced glucose consumption, and a switch to utilize more fatty acids (FA) for energy, a destructive adaptation implicated in cell death. One source of FA available to the heart is through the breakdown of lipoprotein-triglyceride (TG), catalyzed by lipoprotein lipase (LPL) at the coronary lumen. In a model of moderate hypoinsulinemia with hyperglycemia, when circulating albumin-bound FA or TG have yet to increase, an augmented vascular LPL is observed. Conversely, following severe hypoinsulinemia, when plasma FA also increases together with hyperglycemia, luminal LPL is turned off. Chronic management of glycemia in Type 1 diabetes fluctuates, with frequent episodes of insufficient or poor control, as such we continue to examine how pathological oscillations in coronary LPL arise and predispose individuals to DCM.

  • The shift in cardiac metabolism (reduced glucose but greater fatty acid utilization) during diabetes causes cardiovascular complications. This is because, unlike glucose, FA oxidation requires greater amounts of oxygen to produce a similar amount of ATP and the diabetic heart may have a mismatch between FA delivery and provision of O2. This leads to myocyte accumulation of lipid metabolites like diacylglycerols, ceramides and triglycerides (TG) leading to lipotoxicity. Vascular endothelial growth factor B (VEGFB), which is highly expressed in the heart, has shown unique properties affecting coronary vasculature, metabolic reprogramming, cell survival. This growth factor is being studied as part of a novel therapeutic strategy to restore metabolic equilibrium, curb lipotoxicity, and help prevent/delay the heart dysfunction characteristic of diabetes.

  • In addition to cardiomyocytes, endothelial cells (EC) make up a significant proportion of the heart, with the majority of ATP generation in these cells provided by glucose. EC metabolism is also altered following diabetes, and the two cell types are interdependent for normal functioning, and changes in their respective metabolism will synergistically induce cardiac failure. EC can respond to environmental cues, such as hyperglycemia, by secreting paracrine factors like heparanase. Heparanase is an endoglycosidase that is critical to the regulation of LPL. It can cleave heparan sulfate chains of proteoglycans (HSPGs) located on cell surfaces, therefore releasing membrane-bound proteins. Thus, once heparanase is secreted by EC, it can release proteins like LPL from its cell surface-bound position for onward translocation to the luminal surface of the blood vessels and TG lipolysis. This cross-talk is expected to facilitate FA delivery and utilization by the cardiomyocyte. Our lab is further exploring how the EC act as “first-responders” to environmental cues, and how they communicate with the underlying cardiomyocytes during diabetes. 

Selection of Publications

Complete list of publications available on Pubmed: http://www.ncbi.nlm.nih.gov/pubmed?term=rodrigues+brian

  • Lee CS, Shang R, Wang F, Khayambashi P, Wang H, Araujo G, Puri K, Vlodavsky I, Hussein B, Rodrigues B. Heparanase Stimulation of Physiologic Cardiac Hypertrophy Is Suppressed After Chronic Diabetes, Resulting in Cardiac Remodeling and Dysfunction. Diabetes. 2024 Aug 1;73(8):1300-1316. doi: 10.2337/db24-0217

  • Shang R, Lee CS, Wang H, Dyer R, Noll C, Carpentier A, Sultan I, Alitalo K, Boushel R, Hussein B, Rodrigues B. Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization. Arterioscler Thromb Vasc Biol. 2024 Jan;44(1):177-191. doi: 10.1161/ATVBAHA.123.319972

  • Lee CS, Zhai Y, Shang R, Wong T, Mattison AJ, Cen HH, Johnson JD, Vlodavsky I, Hussein B, Rodrigues B. Flow-Induced Secretion of Endothelial Heparanase Regulates Cardiac Lipoprotein Lipase and Changes Following Diabetes. J Am Heart Assoc. 2022 Dec 6;11(23):e027958. doi: 10.1161/JAHA.122.027958

  • Shang R, Lal N, Lee CS, Zhai Y, Puri K, Seira O, Boushel RC, Sultan I, Räsänen M, Alitalo K, Hussein B, Rodrigues B. Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart. Am J Physiol Endocrinol Metab. 2021 Dec 1;321(6):E753-E765. doi: 10.1152/ajpendo.00219.2021

  • Shang R, Rodrigues B. Lipoprotein Lipase and Its Delivery of Fatty Acids to the Heart. Biomolecules. 2021 Jul 12;11(7):1016. doi: 10.3390/biom11071016

  • Puri K, Lal N, Shang R, Ghosh S, Flibotte S, Dyer R, Hussein B, Rodrigues B. Diabetes Mellitus Severity and a Switch From Using Lipoprotein Lipase to Adipose-Derived Fatty Acid Results in a Cardiac Metabolic Signature That Embraces Cell Death. J Am Heart Assoc. 2019 Nov 5;8(21):e014022. doi: 10.1161/JAHA.119.014022

  • Wang F, Pulinilkunnil T, Flibotte S, Nislow C, Vlodavsky I, Hussein B, Rodrigues B. Heparanase protects the heart against chemical or ischemia/reperfusion injury. J Mol Cell Cardiol. 2019 Jun;131:29-40. doi: 10.1016/j.yjmcc.2019.04.008

  • Zhang D, Wang F, Lal N, Chiu AP, Wan A, Jia J, Bierende D, Flibotte S, Sinha S, Asadi A, Hu X, Taghizadeh F, Pulinilkunnil T, Nislow C, Vlodavsky I, Johnson JD, Kieffer TJ, Hussein B, Rodrigues B. Heparanase Overexpression Induces Glucagon Resistance and Protects Animals From Chemically Induced Diabetes. Diabetes. 2017 Jan;66(1):45-57. doi: 10.2337/db16-0761.

  • Wan A, Rodrigues B. Endothelial cell-cardiomyocyte crosstalk in diabetic cardiomyopathy. Cardiovasc Res. 2016 Aug 1;111(3):172-83. doi: 10.1093/cvr/cvw159

  • Chiu AP, Wan A, Lal N, Zhang D, Wang F, Vlodavsky I, Hussein B, Rodrigues B. Cardiomyocyte VEGF Regulates Endothelial Cell GPIHBP1 to Relocate Lipoprotein Lipase to the Coronary Lumen During Diabetes Mellitus. Arterioscler Thromb Vasc Biol. 2016 Jan;36(1):145-55. doi: 10.1161/ATVBAHA.115.306774

  • Wang Y, Chiu AP, Neumaier K, Wang F, Zhang D, Hussein B, Lal N, Wan A, Liu G, Vlodavsky I, Rodrigues B. Endothelial cell heparanase taken up by cardiomyocytes regulates lipoprotein lipase transfer to the coronary lumen after diabetes. Diabetes. 2014 Aug;63(8):2643-55. doi: 10.2337/db13-1842

Funding Sources