Abstract 4143069: Serum Glucocorticoid Regulated Kinase 1 (SGK-1) Inhibitor Reduced Hypertension in a Salt-Sensitive Hypertension Model of Heart Failure with Preserved Ejection Fraction

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex clinical syndrome marked by multiple cardiac and extracardiac pathophysiological alterations. Despite accounting for 50% of HF diagnoses, treatment options for HFpEF remain limited. Serum and glucocorticoid regulated kinase 1 (SGK1), a PI3-kinase-dependent kinase, is demonstrated to play a role in HF and atrial fibrillation. Hypothesis: Based on the role of SGK1 in renal sodium homeostasis, inflammation, and fibrosis, we hypothesized that SGK1 inhibition would prevent the progression of HFpEF. This hypothesis was tested by assessing the efficacy of a novel and potent SGK1 inhibitor, SGK1-I, in a rat model of HFpEF. Methods: Forty Dahl salt sensitive (Dahl SS) rats were fed low salt diet (LSD, 0.3% NaCl) or high salt diet (HSD, 8% NaCl) for a total of 12 weeks. After 6 weeks, rats were treated with vehicle or SGK1-I (10 or 25 mg/kg/day) via oral gavage for an additional 6 weeks. Intracardiac hemodynamics and cardiac structure and function were assayed using pressure volume loop and echocardiography respectively. BP and cardiac structure data from 4-6 animals/group are discussed. Results: Dahl SS rats fed with HSD exhibited increased systolic arterial pressure (SAP; LSD: 85±9.8, HSD: 132±29.4 mmHg, p =0.01) and diastolic arterial blood pressure (DAP; LSD: 152±12.5, HSD: 202.8±27.0 mmHg, p = 0.03); SGK1-I reduced the HFD SAP (10 mg/kg/day: 190±37 mmHg, p=0.13 and 25 mg/kg/day: 164±5 mmHg, p=0.93) and DAP (10 mg/kg/day: 122±29 mmHg, p=0.07 and 25 mg/kg/day: 99±6 mmHg, p=0.84) in a dose dependent manner to the LSD levels. The high dose of SGK1-I also reduced HSD-induced alteration in left ventricular (LV) morphology, including posterior wall thickness (HSD: 2.38±0.32 mm, SGK1-I: 2.21±0.24 mm, p< 0.05) and improved ratio of LV+septum mass to tibia length (HSD: 26.53±0.00 mg/mm, SGK1-I: 25.18±0.00 mg/mm, p<0.05). The dose dependent reduction of left ventricle pressure development and maximal pressure in HSD rats administered with SGK1-I suggests protection is due to alleviation of hypertension induced pressure overload in the heart. Conclusion: Data analyzed to date suggest SGK1-I administration reduces elevations in blood pressure and subsequent alteration in LV morphology in Dahl SS rats fed with HSD. These data support the need for additional preclinical studies to explore the use of SGK1 inhibition as a promising target for the treatment of HFpEF associated with hypertension.