Left Ventricular SGLT1 Protein Expression Correlates with the Extent of Myocardial Nitro-Oxidative Stress in Rats with Pressure and Volume Overload-Induced Heart Failure

Abstract

Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to be upregulated in humans with heart failure (HF) with or without diabetes. In vitro studies have linked SGLT1 to increased nitro-oxidative stress in cardiomyocytes. We aimed to assess the relation between left ventricular (LV) SGLT1 expression and the extent of nitro-oxidative stress in two non-diabetic rat models of chronic heart failure (HF) evoked by either pressure (TAC, n = 12) or volume overload (ACF, n = 12). Sham-operated animals (Sham-T and Sham-A, both n = 12) served as controls. Both TAC and ACF induced characteristic LV structural and functional remodeling. Western blotting revealed that LV SGLT1 protein expression was significantly upregulated in both HF models (both p < 0.01), whereas the phosphorylation of ERK1/2 was decreased only in ACF; AMPKα activity was significantly reduced in both models. The protein expression of the Nox4 NADPH oxidase isoform was increased in both TAC and ACF compared with respective controls (both p < 0.01), showing a strong positive correlation with SGLT1 expression (r = 0.855, p < 0.001; and r = 0.798, p = 0.001, respectively). Furthermore, SGLT1 protein expression positively correlated with the extent of myocardial nitro-oxidative stress in failing hearts assessed by 3-nitrotyrosin (r = 0.818, p = 0.006) and 4-hydroxy-2-nonenal (r = 0.733, p = 0.020) immunostaining. Therefore, LV SGLT1 protein expression was upregulated irrespective of the nature of chronic hemodynamic overload, and correlated significantly with the expression of Nox4 and with the level of myocardial nitro-oxidative stress, suggesting a pathophysiological role of SGLT1 in HF.

Effects of SGLT2 Inhibitors beyond Glycemic Control—Focus on Myocardial SGLT1

“…We also reported that canagliflozin blunts oxidative stress in non-diabetic rats with acute myocardial ischemia-reperfusion injury [80]. In line with these, we showed that LV SGLT1 expression is upregulated in non-diabetic rats with HF, irrespective of whether chronic pressure (transverse aortic constriction, TAC) or volume (aortocaval fistula) overload was the underlying pathophysiology [60]. The expression of SGLT1 showed a robust correlation with the extent of myocardial nitro-oxidative stress in rats with HF [60].…”

“…In line with these, we showed that LV SGLT1 expression is upregulated in non-diabetic rats with HF, irrespective of whether chronic pressure (transverse aortic constriction, TAC) or volume (aortocaval fistula) overload was the underlying pathophysiology [60]. The expression of SGLT1 showed a robust correlation with the extent of myocardial nitro-oxidative stress in rats with HF [60]. Mouse neonatal cardiomyocytes with genetically ablated SGLT1 are resistant to in vitro hypertrophic stimuli, whereas mice with global SGLT1 knockout are protected from the development of pathological LV hypertrophy in response to chronic pressure overload induced by TAC [59].…”

“…In line with data on human hearts, myocardial SGLT1 mRNA or protein expression was found to be upregulated in non-diabetic small animal models of acute myocardial ischemia-reperfusion injury [55] or ischemic preconditioning [56], permanent LAD ligation (model of ICM) [51,57,58], and hemodynamic-overload induced HF [59,60], as well as in models of metabolic syndrome and T2DM [51,54,[61][62][63][64]. Interestingly, SGLT1 was downregulated in mice with streptozotocin-induced type 1 diabetes mellitus (T1DM) [51].…”

“…In a genetic model of HF, overactivation of AMPK resulted in substantial upregulation of myocardial SGLT1 [ 68 , 69 ]. In rats with chronic pressure overload-induced HF, we found increased LV SGLT1 expression with preserved ERK1/2 phosphorylation [ 60 ]. On the contrary, HF due to chronic volume overload was associated with comparable upregulation of SGLT1 but significantly lower ERK1/2 phosphorylation, whereas AMPK activity was diminished in both models [ 60 ].…”

“…In rats with chronic pressure overload-induced HF, we found increased LV SGLT1 expression with preserved ERK1/2 phosphorylation [ 60 ]. On the contrary, HF due to chronic volume overload was associated with comparable upregulation of SGLT1 but significantly lower ERK1/2 phosphorylation, whereas AMPK activity was diminished in both models [ 60 ]. Therefore, in chronic HF, other mediators might contribute to maintaining increased SGLT1 expression, although a negative association between ERK1/2 activation and SGLT1 expression has been noted in primary cultured rabbit renal proximal tubule cells [ 70 , 71 ] and in humans with end-stage HF [ 41 ].…”