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.
Highlights
In animals of the transverse aortic constriction (TAC) group, chronic pressure overload resulted in severe left ventricular (LV) hypertrophy according to gradually increasing LV mass throughout the follow-up period (PTAC < 0.001), which was substantially higher at Week 14 as compared with Sham-T controls (p < 0.001) (Figure 1A)
(D) LV ejection fraction (EF), end-systolic pressure-volume relationship (ESPVR) and time constant of LV pressure decay (Tau) in Sham-T and TAC groups. (E) LV myocardial mRNA expression of pathological hypertrophy markers β/α-myosin heavy chain (β/α-MHC), collagen type I alpha 1 (Col1a1), connective tissue growth factor (CTGF), and transforming growth factor beta (TGF-β). (F) Temporal changes in LV mass according to the Sham-A and volume-overloaded (ACF) groups. (G)
We demonstrate for the first time that TAC-induced chronic heart failure (HF) for 14 weeks is associated with increased LV sodium-glucose cotransporter 1 (SGLT1) expression on the protein level, in line with upregulation of the mRNA expression of pathological hypertrophy markers
Summary
Sodium-glucose cotransporter 1 (SGLT1) has recently been identified as a major glucose transporter in the heart [1]. We previously showed that left ventricular (LV) SGLT1 is upregulated in patients with end-stage heart failure (HF) compared with non-failing controls [2]. In these patients, SGLT1 expression showed a significant correlation with the extent of LV dilation and systolic dysfunction independent of age, sex, and body mass index [2]. Knockout or knockdown of SGLT1 prevents LV pathological remodeling in murine models of pressure overload [3] or type 2 diabetes mellitus (T2DM) [4,5], whereas humans with functionally limited SGLT1 have substantially lower risk of developing HF 4.0/).
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