Left ventricular SGLT1 expression correlates with the extent of myocardial nitro-oxidative stress in rat models of heart failure

Abstract

Abstract Introduction Recently, selective sodium glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce hospitalization for heart failure (HF) in patients with HF, irrespective of type 2 diabetes mellitus (T2DM). The mechanism of action is currently unclear as SGLT2 is not expressed in the heart. Unlike selective SGLT2 inhibitors, the dual SGLT1/2 inhibitor sotagliflozin not only reduced hospitalization for HF, but also decreased the risk of myocardial infarction, suggesting cytoprotective action. Even though SGLT1 it highly expressed in the sarcolemma of cardiomyocytes, its pathophysiological role is unclear. Previous studies have postulated that SGLT1 propagates nitro-oxidative stress in cardiomyocytes through NADPH oxidases. Purpose We aimed to assess myocardial left ventricular (LV) SGLT1 protein expression in two rat models of chronic heart failure and assess possible downstream effectors. Methods We evoked chronic HF in male rats by pressure overload using transverse aortic constriction (TAC, n=7) or by volume overload using aorto-caval fistula (ACF, n=7). Respective sham operated animals (Sham-T or Sham-A, both n=7) served as controls. At the end of the protocol, LV function was assessed using echocardiography and invasive pressure-volume analysis. Myocardial protein expression analysis was performed by western blotting, whereas nitro-oxidative stress was quantified by immunohistochemical staining for 3-nitrotyrosine (3-NT). Results In both TAC and ACF, systolic and diastolic dysfunction was evident, whereas LV mass was significantly increased compared with respective controls. The LV protein expression of SGLT1 was significantly upregulated in both HF models (∼1.5-fold increase, both P<0.01). Whereas the phosphorylation of ERK1/2 was decreased only in ACF, AMPKα activity was significantly reduced in both types of HF. The protein expression of the Nox4 NADPH isoform was substantially upregulated in both TAC and ACF (both P<0.01). The expression of SGLT1 and Nox4 showed a strong positive correlation in the Sham-T plus TAC (r=0.855, P<0.001) and Sham-A plus ACF (r=0.798, P=0.001) cohorts, respectively. Furthermore, SGLT1 expression positively correlated with the extent of myocardial nitro-oxidative stress as assessed by 3-NT staining (Sham-T plus TAC: r=0.833, P=0.015; Sham-A plus ACF: r=0.762, P=0.037). Conclusions LV SGLT1 protein expression was upregulated in both pressure and volume overload-induced HF, irrespective of aetiology, and correlated significantly with Nox4 expression and with the extent of myocardial nitro-oxidative stress. These suggest that SGLT1 might play an important role in the pathophysiology of HF. Future studies should elucidate the possible link between the upregulation of SGLT1 in HF and the increase of myocardial nitro-oxidative stress, so that the salutary effects of the dual SGLT1/2 inhibitor sotagliflozin could be partially explained. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Fund of Hungary (NVKP_16-1-2016-0017)Ministry for Innovation and Technology in Hungary (2020-4.1.1.-TKP2020)National Research, Development and Innovation Office (NKFIH) of Hungary (K134939 to TR)