Empagliflozin prevents angiotensin II-induced hypertension related micro and macrovascular endothelial cell activation and diastolic dysfunction in rats despite persistent hypertension: Role of endothelial SGLT1 and 2

Bruckert, C; Matsushita, Kensuke; Mroueh, Ali; Amissi, Said; Auger, Cyril; Houngue, Ursula; Remila, Lamia; Chaker, Ahmed; Park, Sin‐Hee; Algara-Suárez, Paola; Belcastro, Eugenia; Jesel, Laurence; Ohlmann, Patrick; Morel, Olivier; Schini‐Kerth, Valérie B.

doi:10.1016/j.vph.2022.107095

Cited by 16 publications

(7 citation statements)

References 32 publications

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“… 34 , 35 The underlying mechanisms have been partly elucidated by clinical and preclinical studies including ours, demonstrating the cardioprotective effects of SGLT2 inhibitors on left ventricular fibrosis and diastolic dysfunction, pulmonary artery remodeling, coronary microvascular disorder, endothelial dysfunction, inflammation, and oxidative stress. 36 , 37 In the latest European Society of Cardiology guidelines, these drugs are now considered an evidence‐based oral medication for patients with chronic HF. Nevertheless, future studies are warranted to investigate the impact of SGLT2 inhibitors and the combination of the 4 new GDMT drugs on patients with post‐CS.…”

Section: Discussionmentioning

confidence: 99%

Optimal Heart Failure Medical Therapy and Mortality in Survivors of Cardiogenic Shock: Insights From the FRENSHOCK Registry

Matsushita,

Delmas,

Marchandot

et al. 2024

JAHA

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Background The effects of pharmacological therapy on cardiogenic shock (CS) survivors have not been extensively studied. Thus, this study investigated the association between guideline‐directed heart failure (HF) medical therapy (GDMT) and one‐year survival rate in patients who are post‐CS. Methods and Results FRENSHOCK (French Observatory on the Management of Cardiogenic Shock in 2016) registry was a prospective multicenter observational survey, conducted in metropolitan French intensive care units and intensive cardiac care units. Of 772 patients, 535 patients were enrolled in the present analysis following the exclusion of 217 in‐hospital deaths and 20 patients with missing medical records. Patients with triple GDMT (beta‐blockers, renin‐angiotensin system inhibitors, and mineralocorticoid receptor antagonists) at discharge (n=112) were likely to have lower left ventricular ejection fraction on admission and at discharge compared with those without triple GDMT (n=423) (22% versus 28%, P <0.001 and 29% versus 37%, P <0.001, respectively). In the overall cohort, the one‐year mortality rate was 23%. Triple GDMT prescription was significantly associated with a lower one‐year all‐cause mortality compared with non‐triple GDMT (adjusted hazard ratio 0.44 [95% CI, 0.19–0.80]; P =0.007). Similarly, 2:1 propensity score matching and inverse probability treatment weighting based on the propensity score demonstrated a lower incidence of one‐year mortality in the triple GDMT group. As the number of HF drugs increased, a stepwise decrease in mortality was observed (log rank; P <0.001). Conclusions In survivors of CS, the one‐year mortality rate was significantly lower in those with triple GDMT. Therefore, this study suggests that intensive HF therapy should be considered in patients following CS.

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Section: Discussionmentioning

confidence: 99%

Optimal Heart Failure Medical Therapy and Mortality in Survivors of Cardiogenic Shock: Insights From the FRENSHOCK Registry

Matsushita,

Delmas,

Marchandot

et al. 2024

JAHA

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“…In line with this evidence, our results also demonstrate that other mechanisms, such as the local modulation of inflammatory infiltrates and sympathetic activity, are able to counteract the development of myocardial damage caused by Ang II infusion. Both in the case of the infusion of Ang II at a dosage of 200 ng/kg/min for 2 weeks, which we used in the present study, and in the case of a dosage of 520 ng/kg/min [ 34 ] or 0.4 mg/kg/day [ 14 ] for 4 weeks, the cardioprotective effects of the two SGLT2 inhibitors, empagliflozin and dapagliflozin, occur in the presence of high blood pressure values caused by Ang II.…”

Section: Discussionmentioning

confidence: 99%

“…In Ang II-dependent hypertension [ 11 ] and in cyclosporine nephropathy [ 12 ], in the absence of diabetes, empagliflozin prevented renal glomerular and tubulointerstitial damage, while in hypertensive N(w)-nitro-L-arginine methyl ester-treated, renin–transgenic (mRen2)27 rats, empagliflozin alone and/or in combination with finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduced myocardial and renal fibrosis, proteinuria, and allowed to take control of plasma creatinine and blood pressure [ 13 ]. Empagliflozin administration improved diastolic dysfunction and myocardial remodeling in Ang II-dependent hypertension [ 14 ], preserved the myocardial function in rats with cardiorenal syndrome [ 15 ], improved left ventricular function and promoted nephroprotective effects in spontaneously hypertensive rats expressing the human C-reactive protein [ 16 ], a non-diabetic model of metabolic syndrome. In these non-diabetic experimental models, the protective effect of SGLT2 inhibition on organ damage appears, al least in part, due to an anti-inflammatory mechanism [ 11 , 12 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Empagliflozin administration improved diastolic dysfunction and myocardial remodeling in Ang II-dependent hypertension [ 14 ], preserved the myocardial function in rats with cardiorenal syndrome [ 15 ], improved left ventricular function and promoted nephroprotective effects in spontaneously hypertensive rats expressing the human C-reactive protein [ 16 ], a non-diabetic model of metabolic syndrome. In these non-diabetic experimental models, the protective effect of SGLT2 inhibition on organ damage appears, al least in part, due to an anti-inflammatory mechanism [ 11 , 12 , 14 , 15 , 16 ]. Modulation of the sympathetic nervous system has been suggested as a potential mechanism of action implicated in the cardioprotective effects of SGLT2 inhibitors [ 17 , 18 , 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Cardioprotective Effects of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension Are Mediated by the Local Reduction of Sympathetic Activity and Inflammation

Castoldi

Carletti

Ippolito

et al. 2023

IJMS

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The cardioprotective effects of sodium glucose cotrasponter 2 (SGLT2) inhibitors seem to be independent from the effects on glycemic control, through little-known mechanisms. In this study, we investigate whether the cardioprotective effects of empagliflozin, a SGLT2 inhibitor, may be associated with myocardial sympathetic activity and inflammatory cell infiltration in an experimental model of angiotensin II-dependent hypertension. Angiotensin II (Ang II), Ang II plus Empagliflozin, physiological saline, or physiological saline plus empagliflozin were administered to Sprague Dawley rats for two weeks. Blood pressure was measured by plethysmographic method. Myocardial hypertrophy and fibrosis were analysed by histomorphometry, and inflammatory cell infiltration and tyrosine hydroxylase expression, implemented as a marker of sympathetic activity, were evaluated by immunohistochemistry. Ang II increased blood pressure, myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase expression, as compared to the control group. Empagliflozin administration prevented the development of myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase overexpression in Ang II-treated rats, without affecting blood glucose and the Ang II-dependent increase in blood pressure. These data demonstrate that the cardioprotective effects of SGLT2 inhibition in Ang II-dependent hypertension may result from the myocardial reduction of sympathetic activity and inflammation and are independent of the modulation of blood pressure and blood glucose levels.

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“…The use of sodium-glucose cotransporter-2 (SGLT2) inhibitors prevented the stimulating effect of Ang II on ICAM-1, MCP-1, and VCAM-1, and also inhibited collagen I synthesis, and MMP-2 and MMP9 metalloproteinases. The results of the study suggested that treatment with empagliflozin weakens ongoing pro-atherosclerotic processes and other processes affecting vascular endothelial remodeling [ 172 ].…”

Section: Sodium-glucose Cotransporter-2 (Sglt2) Inhibitorsmentioning

confidence: 99%

The Impact of Pharmacotherapy for Heart Failure on Oxidative Stress—Role of New Drugs, Flozins

Bodnar,

Mazurkiewicz,

Chwalba

et al. 2023

Biomedicines

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Heart failure (HF) is a multifactorial clinical syndrome involving many complex processes. The causes may be related to abnormal heart structure and/or function. Changes in the renin-angiotensin-aldosterone system, the sympathetic nervous system, and the natriuretic peptide system are important in the pathophysiology of HF. Dysregulation or overexpression of these processes leads to changes in cardiac preload and afterload, changes in the vascular system, peripheral vascular dysfunction and remodeling, and endothelial dysfunction. One of the important factors responsible for the development of heart failure at the cellular level is oxidative stress. This condition leads to deleterious cellular effects as increased levels of free radicals gradually disrupt the state of equilibrium, and, as a consequence, the internal antioxidant defense system is damaged. This review focuses on pharmacotherapy for chronic heart failure with regard to oxidation–reduction metabolism, with special attention paid to the latest group of drugs, SGLT2 inhibitors—an integral part of HF treatment. These drugs have been shown to have beneficial effects by protecting the antioxidant system at the cellular level.

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Empagliflozin prevents angiotensin II-induced hypertension related micro and macrovascular endothelial cell activation and diastolic dysfunction in rats despite persistent hypertension: Role of endothelial SGLT1 and 2

Cited by 16 publications

References 32 publications

Optimal Heart Failure Medical Therapy and Mortality in Survivors of Cardiogenic Shock: Insights From the FRENSHOCK Registry

Optimal Heart Failure Medical Therapy and Mortality in Survivors of Cardiogenic Shock: Insights From the FRENSHOCK Registry

Cardioprotective Effects of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension Are Mediated by the Local Reduction of Sympathetic Activity and Inflammation

The Impact of Pharmacotherapy for Heart Failure on Oxidative Stress—Role of New Drugs, Flozins

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