Metformin Ameliorates Diabetic Cardiomyopathy by Activating the PK2/PKR Pathway

Yang, Zhen; Wang, Min; Zhang, Yuchen; Cai, Fei; Jiang, Bo; Zha, Wenliang; Yu, Wei

doi:10.3389/fphys.2020.00425

Cited by 34 publications

(23 citation statements)

References 44 publications

(43 reference statements)

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“…Met administration induces the expression of PK2, PKR1, and PKR2 in cardiomyocytes and testis, which provides beneficial effects against diabetes-related cardiac and testicular damage by regulating the AKT/GSK3β pathway. This finding confirms previous data showing that PK2 is involved in cardiac muscle survival and angiogenesis through the AKT and STAT3 pathway [ 79 , 80 ]. Insulin resistance leads to secondary hyperinsulinemia, which is crucial for pregnancy complications such as recurrent miscarriage and preeclampsia, as well as metabolic disorders such as polycystic ovary syndrome (PCOS).…”

Section: Control Of Energy Metabolismsupporting

confidence: 93%

Versatile Role of Prokineticins and Prokineticin Receptors in Neuroinflammation

Lattanzi

Miele

2021

Biomedicines

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Prokineticins are a new class of chemokine-like peptides involved in a wide range of biological and pathological activities. In particular, prokineticin 2 (PK2), prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2) play a central role in modulating neuroinflammatory processes. PK2 and PKRs, which are physiologically expressed at very low levels, are strongly upregulated during inflammation and regulate neuronal-glial interaction. PKR2 is mainly overexpressed in neurons, whereas PKR1 and PK2 are mainly overexpressed in astrocytes. Once PK2 is released in inflamed tissue, it is involved in both innate and adaptive responses: it triggers macrophage recruitment, production of pro-inflammatory cytokines, and reduction of anti-inflammatory cytokines. Moreover, it modulates the function of T cells through the activation of PKR1 and directs them towards a pro-inflammatory Th1 phenotype. Since the prokineticin system appears to be upregulated following a series of pathological insults leading to neuroinflammation, we will focus here on the involvement of PK2 and PKRs in those pathologies that have a strong underlying inflammatory component, such as: inflammatory and neuropathic pain, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, stroke, obesity, diabetes, and gastrointestinal inflammation.

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Section: Control Of Energy Metabolismsupporting

confidence: 93%

Versatile Role of Prokineticins and Prokineticin Receptors in Neuroinflammation

Lattanzi

Miele

2021

Biomedicines

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“…But, in one meta-analysis of nearly 34,000 patients, metformin was associated with reduced mortality in patients with heart failure compared with controls [ 156 ]. Furthermore, it has been shown that metformin is associated with improved cardiac function and alleviation of apoptosis in diabetic mice, as well as protection of cultured cardiomyocytes from cell death during exposure to H 2 O 2 via AMPK activation [ 157 , 158 ].…”

Section: Therapeutic Possibilitiesmentioning

confidence: 99%

The Mystery of Diabetic Cardiomyopathy: From Early Concepts and Underlying Mechanisms to Novel Therapeutic Possibilities

Rotkvić

Planinić

Pršo

et al. 2021

IJMS

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Diabetic patients are predisposed to diabetic cardiomyopathy, a specific form of cardiomyopathy which is characterized by the development of myocardial fibrosis, cardiomyocyte hypertrophy, and apoptosis that develops independently of concomitant macrovascular and microvascular diabetic complications. Its pathophysiology is multifactorial and poorly understood and no specific therapeutic guideline has yet been established. Diabetic cardiomyopathy is a challenging diagnosis, made after excluding other potential entities, treated with different pharmacotherapeutic agents targeting various pathophysiological pathways that need yet to be unraveled. It has great clinical importance as diabetes is a disease with pandemic proportions. This review focuses on the potential mechanisms contributing to this entity, diagnostic options, as well as on potential therapeutic interventions taking in consideration their clinical feasibility and limitations in everyday practice. Besides conventional therapies, we discuss novel therapeutic possibilities that have not yet been translated into clinical practice.

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“…Growing evidence suggests the involvement of other targets including fructose-1,6-bisphosphatase, mechanistic target of rapamycin (mTOR) or mitochondrial glycerol phosphate-dehydrogenase, which are also involved in cellular energy metabolism (Soukas et al, 2019). More recently, an experimental study suggests that the prokineticin (PK) 2/PK receptor (PKR) pathway plays a crucial role in the pathogenesis of diabetic cardiomyopathy and that metformin prevents diabetes-induced glucose and lipid metabolism dysfunction, cardiomyocyte apoptosis, fibrosis, and cardiac insufficiency by stimulating PK2/PKR and the downstream AKT/GSK3β pathway (Yang et al, 2020).…”

Section: Direct Cardiac Effects Question the Molecular Targetmentioning

confidence: 99%

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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Metformin Ameliorates Diabetic Cardiomyopathy by Activating the PK2/PKR Pathway

Abstract: Yang et al.Metformin Ameliorates Diabetic Cardiomyopathy after intervention with PKRA7 or the AKT inhibitor. These results suggest that Met can activate the PK2/PKR-mediated AKT/GSK3β pathway, thus improving cardiac function and alleviating apoptosis in DM mice.

Cited by 34 publications

References 44 publications

Versatile Role of Prokineticins and Prokineticin Receptors in Neuroinflammation

Versatile Role of Prokineticins and Prokineticin Receptors in Neuroinflammation

The Mystery of Diabetic Cardiomyopathy: From Early Concepts and Underlying Mechanisms to Novel Therapeutic Possibilities

Repurposing Antidiabetic Drugs for Cardiovascular Disease

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