Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury

Tanajak, Pongpan; Sa‐nguanmoo, Piangkwan; Sivasinprasasn, Sivaporn; Thummasorn, Savitree; Siri‐Angkul, Natthaphat; Chattipakorn, Nipon

doi:10.1530/joe-17-0457

Cited by 99 publications

(89 citation statements)

References 39 publications

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“…Based on these previous findings, it is possible that, in our current study, selective SGLT2-inhibitors exerted direct cardioprotective effects, although further studies will be needed in order to investigate the effects of those pharmacological agents on cardiac NHE under diabetic insulin-resistant conditions as well as on cardiac fibrosis through histopathological analyses. Regardless, the present study investigated the transient local direct effects of SGLT2inhibitors on the cardiac tissue during the acute phase of IRI; our findings therefore do not conflict with the consistent cardioprotective results from other in vivo experimental studies [44,[49][50][51][52][53][54][55][56] or clinical trials [31][32][33], all of which investigated the systemic effects of SGLT2-inhibitors over a longer period. Furthermore, the present findings suggest that potential mechanisms underlying the cardiovascular benefits of SGLT2-inhibitors may depend largely on the systemic inter-organ network, including cardiorenal syndrome [57][58][59].…”

Section: Discussionsupporting

confidence: 52%

Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity

Yoshii

Nagoshi

Kashiwagi

et al. 2019

Cardiovasc Diabetol

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Background: Recent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac sodium-glucose cotransporter (SGLT1 is the dominant isoform) compared with those of other glucose transporters (insulin-dependent GLUT4 is the major isoform) remain incompletely understood. Given that glucose is an important preferential substrate for myocardial energy metabolism under conditions of ischemia-reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during the acute phase of IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes. Methods and results: The hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either the non-selective SGLT-inhibitor phlorizin or selective SGLT2-inhibitors (tofogliflozin, ipragliflozin, canagliflozin) during IRI using Langendorff model. After ischemia-reperfusion, HFD impaired left ventricular developed pressure (LVDP) recovery compared with the findings in NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and a dramatically increased infarct size were observed in HFD with phlorizin-perfusion. Meanwhile, none of the SGLT2-inhibitors significantly affected cardiac function or myocardial injury after ischemia-reperfusion under either diet condition. The plasma membrane expression of GLUT4 was significantly increased after IRI in NFD but was substantially attenuated in HFD, the latter of which was associated with a significant reduction in myocardial glucose uptake. In contrast, SGLT1 expression at the plasma membrane remained constant during IRI, regardless of the diet condition, whereas SGLT2 was not detected in the hearts of any mice. Of note, phlorizin considerably reduced myocardial glucose uptake after IRI, particularly in HFD. Conclusions: Cardiac SGLT1 but not SGLT2 plays a compensatory protective role during the acute phase of IRI via enhanced glucose uptake, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised.

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Section: Discussionsupporting

confidence: 52%

Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity

Yoshii

Nagoshi

Kashiwagi

et al. 2019

Cardiovasc Diabetol

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“…This is consistent with our observation that EMPA restored mtDNA damage, mtDNA/nDNA ratio and restored PGC1‐α expression, indicating that the effects of SGLT2i on mitochondrial biogenesis can be translated to the non‐diabetic failing heart. Third, the changes in PDH activity and the expression levels of CPT1, GLUT4 and PDK4 observed by us and by others, suggest that the myocardial capacity to oxidize glucose and fatty acids is improved by EMPA. Verma et al .…”

Section: Discussionsupporting

confidence: 49%

“…Second, several studies have suggested that SGLT2i can restore cardiac mitochondrial dysfunction. Indeed, the SGLT2i dapagliflozin restored cardiac PGC1‐α in pre‐diabetic rats . PGC1‐α is a critical mediator of mitochondrial biogenesis and the reductions in PGC1‐α are thought to contribute to mitochondrial dysfunction observed in HF.…”

Section: Discussionmentioning

confidence: 99%

Sodium–glucose co‐transporter 2 inhibition with empagliflozin improves cardiac function in non‐diabetic rats with left ventricular dysfunction after myocardial infarction

Yurista

Silljé

Oberdorf‐Maass

et al. 2019

European J of Heart Fail

254

252

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AimsSodium-glucose co-transporter 2 (SGLT2) inhibition reduces heart failure hospitalizations in patients with diabetes, irrespective of glycaemic control. We examined the effect of SGLT2 inhibition with empagliflozin (EMPA) on cardiac function in non-diabetic rats with left ventricular (LV) dysfunction after myocardial infarction (MI).Non-diabetic male Sprague-Dawley rats underwent permanent coronary artery ligation to induce MI, or sham surgery. Rats received chow containing EMPA that resulted in an average daily intake of 30 mg/kg/day or control chow, starting before surgery (EMPA-early) or 2 weeks after surgery (EMPA-late). Cardiac function was assessed using echocardiography and histological and molecular markers of cardiac remodelling and metabolism were assessed in the left ventricle. Renal function was assessed in metabolic cages. EMPA increased urine production by two-fold without affecting creatinine clearance and serum electrolytes. EMPA did not influence MI size, but LV ejection fraction (LVEF) was significantly higher in the EMPA-early and EMPA-late treated MI groups compared to the MI group treated with vehicle (LVEF 54%, 52% and 43%, respectively, all P < 0.05). EMPA also attenuated cardiomyocyte hypertrophy, diminished interstitial fibrosis and reduced myocardial oxidative stress. EMPA treatment reduced mitochondrial DNA damage and stimulated mitochondrial biogenesis, which was associated with the normalization of myocardial uptake and oxidation of glucose and fatty acids. EMPA increased circulating ketone levels as well as myocardial expression of the ketone body transporter and two critical ketogenic enzymes, indicating that myocardial utilization of ketone bodies was increased. Together these metabolic changes were associated with an increase in cardiac ATP production.

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“…Another SGLT2i, dapagliflozin significantly improved LV EF in a HF model that was creased by coronary artery ligation/reperfusion on high-fat diet-induced pre-diabetic Wistar rats. The biological mechanisms on cardioprotection of 4-week dapagliflozin were suggested from a combination of modulation of mitochondrial DRP1, caspase 3, and lipid peroxidation [30]. The LV EF was not significantly improved by 12-week empagliflozin in our hypertensive heart failure model.…”

Section: Discussionmentioning

confidence: 68%

The sodium–glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats

Lee

Shiou

Jhuo

et al. 2019

Cardiovasc Diabetol

148

113

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Background: Sodium glucose co-transporter 2 inhibitor (SGLT2i), a new class of anti-diabetic drugs acting on inhibiting glucose resorption by kidneys, is shown beneficial in reduction of heart failure hospitalization and cardiovascular mortality. The mechanisms remain unclear. We hypothesized that SGLT2i, empagliflozin can improve cardiac hemodynamics in non-diabetic hypertensive heart failure. Methods and results: The hypertensive heart failure model had been created by feeding spontaneous hypertensive rats (SHR) with high fat diet for 32 weeks (total n = 13). Half SHRs were randomized to be administered with SGLT2i, empagliflozin at 20 mg/kg/day for 12 weeks. After evaluation of electrocardiography and echocardiography, invasive hemodynamic study was performed and followed by blood sample collection and tissue analyses. Empagliflozin exhibited cardiac (improved atrial and ventricular remodeling) and renal protection, while plasma glucose level was not affected. Empagliflozin normalized both end-systolic and end-diastolic volume in SHR, in parallel with parameters in echocardiographic evaluation. Empagliflozin also normalized systolic dysfunction, in terms of the reduced maximal velocity of pressure incline and the slope of end-systolic pressure volume relationship in SHR. In histological analysis, empagliflozin significantly attenuated cardiac fibrosis in both atrial and ventricular tissues. The upregulation of atrial and ventricular expression of PPARα, ACADM, natriuretic peptides (NPPA and NPPB), and TNF-α in SHR, was all restored by treatment of empagliflozin. Conclusions: Empagliflozin improves hemodynamics in our hypertensive heart failure rat model, associated with renal protection, attenuated cardiac fibrosis, and normalization of HF genes. Our results contribute some understanding of the pleiotropic effects of empagliflozin on improving heart function.

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Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury

Cited by 99 publications

References 39 publications

Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity

Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity

Sodium–glucose co‐transporter 2 inhibition with empagliflozin improves cardiac function in non‐diabetic rats with left ventricular dysfunction after myocardial infarction

The sodium–glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats

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