Proteomic Profiling of SGLT-2 Inhibitor Canagliflozin in a Swine Model of Chronic Myocardial Ischemia
Dwight D. Harris,
Sharif A. Sabe,
Mark Broadwin,
Christopher Stone,
Cynthia Xu,
Jiayu Hu,
Meghamsh Kanuparthy,
M. Ruhul Abid,
Frank W. Sellke
Affiliations
Dwight D. Harris
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA
Sharif A. Sabe
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA
Mark Broadwin
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA
Christopher Stone
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA
Cynthia Xu
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA
Jiayu Hu
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA
Meghamsh Kanuparthy
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA
M. Ruhul Abid
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA
Frank W. Sellke
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA
Background: Sodium–glucose cotransporter-2 (SGLT2) inhibitors are known to be cardioprotective independent of glucose control, but the mechanisms of these benefits are unclear. We previously demonstrated improved cardiac function and decreased fibrosis in a swine model of chronic myocardial ischemia. The goal of this study is to use high-sensitivity proteomic analyses to characterize specific molecular pathways affected by SGLT-2 inhibitor canagliflozin (CAN) therapy in a swine model of chronic myocardial ischemia. Methods: Chronic myocardial ischemia was induced in sixteen Yorkshire swine via the placement of an ameroid constrictor to the left circumflex coronary artery. After two weeks of recovery, swine received either 300 mg of CAN daily (n = 8) or a control (n = 8). After five weeks of therapy, the group of swine were euthanized, and left ventricular tissue was harvested and sent for proteomic analysis. Results: Total proteomic analysis identified a total of 3256 proteins between the CAN and control groups. Three hundred and five proteins were statistically different. This included 55 proteins that were downregulated (p p 2) with CAN treatment. Pathway analysis demonstrated the upregulation of several proteins involved in metabolism and redox activity in the CAN-treated group. The CAN group also exhibited a downregulation of proteins involved in motor activity and cytoskeletal structure. Conclusions: In our swine model of chronic myocardial ischemia, CAN therapy alters several proteins involved in critical molecular pathways, including redox regulation and metabolism. These findings provide additional mechanistic insights into the cardioprotective effects of canagliflozin.
