Left ventricular SGLT1 expression is upregulated in heart failure in humans and rat model. (10th June 2022)

• Record Type: Journal Article
• Authors: Sayour, AA; Ruppert, M; Olah, A; Barta, BA; Zsary, E; Benke, K; Horvath, EM; Hartyanszky, I; Merkely, B; Radovits, T
• Is Part Of: Cardiovascular research. Volume 118(2022)Supplement 1
• Publication Date: 2022-06-10
• Subjects: Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvac066.082
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Funding Acknowledgements: Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Fund of Hungary; Ministry of Human Capacities of Hungary Introduction: Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to contribute to cardiac pathological processes, whereas humans with functionally limited SGLT1 are at lower risk of developing heart failure (HF). The novel HF medications, SGLT2 inhibitors, non-selectively inhibit SGLT1 to different extent, therefore, characterization of its expression in disease conditions is relevant. Purpose: To investigate left ventricular (LV) SGLT1 expression in humans with end-stage HF, and in a rat model of HF. Methods: Myocardial LV samples were harvested from control subjects (Controls, n=9) undergoing valve surgery, and from patients with end-stage dilated cardiomyopathy (DCM, n=12) undergoing heart transplantation. The rat model of aorto-caval fistula (ACF, n=12) was used to induce HF with predominant LV dilation in rats during a course of 24 weeks; sham-operated animals served as controls (Sham-A, n=12). Echocardiography was used to assess LV structure and function prior to surgery in humans, as well as in rats at the end of the follow-up period. Western blotting was performed to characterize LV SGLT1 protein expression and to investigate the activity of the master regulators AMPK and ERK1/2. The extent of LV nitro-oxidative stress was quantified by immunohistochemistry (3-nitrotyrosine) in rats with HF. Results: Both humans with DCM and rats with ACF-induced HF presented with severely dilated LVs compared to respective controls, whereas LV SGLT1 protein expression was significantly upregulated similarly by ~1.7-fold in both cases (both P<0.01). These increases in SGLT1 expressions were accompanied by significant reductions in ERK1/2 activating phosphorylation (both P<0.05), whereas AMPK activity was unaffected. In rats with HF, LV SGLT1 expression correlated significantly with the extent of myocardial nitro-oxidative stress (r=0.762, P=0.037). Conclusions: LV SGLT1 expression is upregulated in HF in both humans and small animals, and ERK1/2 shows a concomitantly reduced activity. LV SGLT1 expression correlates with the extent of nitro-oxidative stress, suggesting a possible pathological role in HF. Whether SGLT2 inhibitors exert direct cardiac actions via inhibition of myocardial SGLT1 needs to be elucidated.