Canagliflozin Attenuates Pulmonary TGF Beta Activation in a Porcine Model of Type 2 Pulmonary Hypertension
*Meghamsh Kanuparthy MD1, *Dwight D. Harris 2, *Mark Broadwin MD3, *Christopher Stone MD1, *Jad Hamze 1, Frank Sellke MD1
1Department of Surgery, Brown University, Providence, RI; 2Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA; 3Department of Surgery, Lehigh Valley Medical Center, Allentown, PA
RATIONALE
Type 2 Pulmonary Hypertension, secondary to left heart failure is the most common cause of pulmonary hypertension and has repeatedly been demonstrated to drastically increase morbidity and mortality. In this study, we investigate the use of canagliflozin, an SGLT2 inhibitor commonly used in diabetes management and currently first line therapy in congestive heart failure, on the pulmonary fibrosis in a porcine model of chronic myocardial ischemia.
METHODS
Sixteen Yorkshire swine, eight in a normal diet control arm (NDC) and eight in the canagliflozin arm (CAN) underwent left anterior thoracotomy for the placement of an ameroid constrictor on the left circumflex artery in well-established model of chronic myocardial ischemia. Five weeks after placement, the swine underwent terminal harvest procedure and lung tissue was collected. During harvest, left ventricular contractility was quantified by direct left ventricular cannulation and impedance measurement of pressure-volume loops. Protein expression was quantified by immunoblotting and Masson’s trichrome staining was utilized to assess vessel diameter, wall thickness and perivascular collagen deposition.
RESULTS
Analysis of left ventricular ejection fraction demonstrated no significant difference between CAN and NDC (NDC mean EF = 27.28%, CAN mean EF = 40.63%, p = 0.8879). Western blot analysis demonstrated strong increases in TGFb signaling pathways with decreased expression of free TGFb and TGFb monomers in CAN pigs (p < 0.001 and p = 0.018, respectively). Downstream mediators of TGFb were also increased with a significant increase in phospho-SMAD2/3 activity (p = 0.005). While there was no significant different in SMAD2/3 levels, there was significant difference in p-SMAD2/3 to SMAD2/3 ratios (p = 0.042). There was also increased proliferation of matrix metalloproteinase 9 in NDC as compared to CAN (p = 0.002). Analysis of other chronic inflammatory markers TNFa, IL6, and other pathways associated with chronic fibrosis PI3K/AKT and JAK2/STAT3 did not demonstrate significant differences (p > 0.05). Masson’s Trichrome analysis of lung tissue demonstrated a strong trend towards significance with reduced perivascular collagen deposition in CAN swine lungs (p = 0.086). There was no difference in arteriolar wall diameter or wall thickness to overall vessel thickness diameter (p = 0.204). Immunoblot analysis did not demonstrate a significant difference in COL1A1 (p =0.305).
CONCLUSION
Canagliflozin appears to ameliorate chronic fibrotic changes related to pulmonary hypertension in chronic left ventricular failure. While there was a strong trend towards significance in histologic analysis, this may be limited by the duration of left ventricular failure induced by our model. Western blot analysis, however, demonstrates that canagliflozin’s modulation of TGFbsignaling pathways may play a key role in management of secondary pulmonary hypertension.
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