Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

Packer, Milton

doi:10.1002/ejhf.1732

Cited by 81 publications

(67 citation statements)

References 182 publications

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“…Our previous research proved that the increase of autophagy level helped to restore cardiac function and alleviate cardiac remodeling under hypoxic injury conditions (Hu et al, 2016). On the contrary, if the level of autophagy cannot be increased correspondingly after suffering the injury, it will lead to further deterioration of heart function (Hu et al, 2016;Packer, 2020).…”

Section: Discussionmentioning

confidence: 97%

SHANK3 Co-ordinately Regulates Autophagy and Apoptosis in Myocardial Infarction

Man

Wang

et al. 2020

Front. Physiol.

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Cardiac remodeling and dysfunction are responsible for the high mortality after myocardial infarction (MI). We assessed the potential for Shank3 to alleviate the post-infarction cardiac dysfunction. The experimental MI mice model was constructed by left anterior descending coronary artery ligation. Shank3 knockout aggravated cardiac dysfunction after MI, while Shank3 overexpression alleviated it. The histological examination showed that the infarct size was significantly increased in the acute phase of MI in the Shank3 knockout group, and the cardiac dysfunction of the Shank3 knockout group was even more severe than the Shank3 overexpression group, revealed by echocardiography analyses. In vitro, cultured neonatal cardiomyocytes were subjected to simulated MI. Shank3 downregulation curbed LC3 expression and autophagosome-lysosome fusion. Furthermore, Shank3 downregulation increased cardiomyocyte apoptosis. In contrast, Shank3 upregulation induced autophagy, and inhibited apoptosis under hypoxia. In vivo, western blot analysis showed decreased levels of Atg7, Beclin1, LC3-II, and Bcl-2 as well as increased expression of p62, cleaved caspase-3, and cleaved caspase-9 in the Shank3 knockout group which suffered from MI. On the other hand, it also revealed that Shank3 overexpression induced autophagy and inhibited apoptosis after MI. Shank3 may serve as a new target for improving cardiac function after MI by inducing autophagy while inhibiting apoptosis.

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Section: Discussionmentioning

confidence: 97%

SHANK3 Co-ordinately Regulates Autophagy and Apoptosis in Myocardial Infarction

Man

Wang

et al. 2020

Front. Physiol.

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“…For example, it is known that metformin stimulates autophagy via activating AMPK and sirtuin-1 (SIRT1) and by this way, may contribute to the cardioprotective effects seen in experimental models of HF (Gundewar et al, 2009). Recent studies revealed that SGLT2i may exert cardioprotective effects by stimulating autophagy (Levine et al, 2015), which may involve the activation of AMPK and SIRT1 (Packer, 2020). The overlap in the mechanism of action between metformin and SGLT2i may be the reason for the reduced cardioprotective effects of SGLT2i in patients with metformin treatment at baseline, when compared to the non-metformin group (Packer, 2020).…”

Section: Mechanisms Of Cardioprotection Of the Antidiabetic Drugsmentioning

confidence: 99%

“…Recent studies revealed that SGLT2i may exert cardioprotective effects by stimulating autophagy (Levine et al, 2015), which may involve the activation of AMPK and SIRT1 (Packer, 2020). The overlap in the mechanism of action between metformin and SGLT2i may be the reason for the reduced cardioprotective effects of SGLT2i in patients with metformin treatment at baseline, when compared to the non-metformin group (Packer, 2020).…”

Section: Mechanisms Of Cardioprotection Of the Antidiabetic Drugsmentioning

confidence: 99%

“…Off-target effects on SGLT1 and direct binding of SGLT2i to NHE-1 are questionable but the regulation of Na + , H + , and Ca 2+ in cardiomyocytes and in specific microdomains may contribute to cardioprotective effects of SGLT2i (Pabel et al, 2018). Of note, the increase in haematocrit and levels of erythropoietin through treatment with SGLT2i were recently discussed to trigger autophagy and reduce reactive oxygen species (ROS) in the heart and thus may represent another indirect effect contributing to cardioprotection (Packer, 2020).…”

Section: Direct Cardiac Effects Question the Molecular Targetmentioning

confidence: 99%

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Repurposing Antidiabetic Drugs for Cardiovascular Disease

et al. 2020

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Metabolic diseases and diabetes represent an increasing global challenge for human health care. As associated with a strongly elevated risk of developing atherosclerosis, kidney failure and death from myocardial infarction or stroke, the treatment of diabetes requires a more effective approach than lowering blood glucose levels. This review summarizes the evidence for the cardioprotective benefits induced by antidiabetic agents, including sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP1-RA), along with sometimes conversely discussed effects of dipeptidyl peptidase-4 inhibitor (DPP4i) and metformin in patients with high cardiovascular risk with or without type 2 diabetes. Moreover, the proposed mechanisms of the different drugs are described based on the results of preclinical studies. Recent cardiovascular outcome trials unexpectedly confirmed a beneficial effect of GLP-1RA and SGLT2i in type 2 diabetes patients with high cardiovascular risk and with standard care, which was independent of glycaemic control. These results triggered a plethora of studies to clarify the underlying mechanisms and the relevance of these effects. Taken together, the available data strongly highlight the potential of repurposing the original antidiabetics GLP1-RA and SGLT2i to improve cardiovascular outcome even in non-diabetic patients with cardiovascular diseases.

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“…12 In addition, they cannot be ascribed to natriuretic effect, since diuretic therapy has been associated with increased risk of CVD and mortality in patients with HF. [13][14][15][16] As a consequence, accumulating evidence has been gathered in an attempt to figure out the possible underlying mechanisms of cardioprotection. In view of the rapid decline in risk of HHF, it can be speculated that the benefits of SGLT2Is are due to the direct effects on the heart itself, namely improved DCM, instead of metabolic improvement.…”

Section: Introductionmentioning

confidence: 99%

<p>SGLT2 Inhibitors: A Novel Player in the Treatment and Prevention of Diabetic Cardiomyopathy</p>

Li¹,

Zhou²

2020

DDDT

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Diabetic cardiomyopathy (DCM) characterized by diastolic and systolic dysfunction independently of hypertension and coronary heart disease, eventually develops into heart failure, which is strongly linked to a high prevalence of mortality in people with diabetes mellitus (DM). Sodium-glucose cotransporter type2 inhibitors (SGLT2Is) are a novel type of hypoglycemic agent in increasing urinary glucose and sodium excretion. Excitingly, the EMPA-REG clinical trial proved that empagliflozin significantly reduced the relative risk of cardiovascular (CV) death and hospitalization for heart failure (HHF) in patients with type 2 DM (T2DM) plus CV disease (CVD). The EMPRISE trial showed that empagliflozin decreased the risk of HHF in T2DM patients with and without a CVD history in routine care. These beneficial effects of SGLT2Is could not be entirely attributed to glucose-lowering or natriuretic action. There could be potential direct mechanisms of SGLT2Is in cardioprotection. Recent studies have shown the effects of SGLT2Is on cardiac iron homeostasis, mitochondrial function, anti-inflammation, anti-fibrosis, antioxidative stress, and reninangiotensin-aldosterone system activity, as well as GlcNAcylation in the heart. This article reviews the current literature on the effects of SGLT2Is on DCM in preclinical studies. Possible molecular mechanisms regarding potential benefits of SGLT2Is for DCM are highlighted, with the purpose of providing a novel strategy for preventing DCM.

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Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

Cited by 81 publications

References 182 publications

SHANK3 Co-ordinately Regulates Autophagy and Apoptosis in Myocardial Infarction

SHANK3 Co-ordinately Regulates Autophagy and Apoptosis in Myocardial Infarction

Repurposing Antidiabetic Drugs for Cardiovascular Disease

<p>SGLT2 Inhibitors: A Novel Player in the Treatment and Prevention of Diabetic Cardiomyopathy</p>

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