Double‐stranded RNA‐dependent protein kinase signalling and paradigms of cardiometabolic syndrome

Fundamemntal Clinical Pharma

Bhat

et al. 2018

Self Cite

Double-stranded RNA (dsRNA)-activated protein kinase R (PKR), a ubiquitously expressed serine/threonine kinase, is a key inducer of inflammation, insulin resistance, and glucose homeostasis in obesity. Recent studies have demonstrated that PKR can respond to metabolic stress in mice as well as in humans. However, the underlying molecular mechanism is not fully understood. The aim of this study was to examine the effect of high fructose (HF) in cultured renal tubular epithelial cells (NRK-52E) derived from rat kidney and to investigate whether inhibition of PKR could prevent any deleterious effects of HF in these cells. PKR expression was determined by immunofluorescence staining and Western blotting. Oxidative damage and apoptosis were measured by flow cytometry. HF-treated renal cells developed a significant increase in PKR expression. A significant increase in reactive oxygen species generation and apoptosis was also observed in HF-treated cultured renal epithelial cells. All these effects of HF were attenuated by a selective PKR inhibitor, imoxin (C16). In conclusion, our study demonstrates PKR induces oxidative stress and apoptosis, is a significant contributor involved in vascular complications and is a possible mediator of HF-induced hypertension. Inhibition of PKR pathway can be used as a therapeutic strategy for the treatment of cardiovascular and metabolic disorders.

Section: Discussionmentioning

confidence: 99%

Imoxin attenuates high fructose‐induced oxidative stress and apoptosis in renal epithelial cells via downregulation of protein kinase R pathway

Kalra

Fundamemntal Clinical Pharma

Bhat

et al. 2018

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“…Therefore, there is an unmet need for the identification of novel drug targets that reduce diabetes associated complications. Double‐stranded RNA‐dependent protein kinase (PKR) is a recently explored target because of its activation under obese and insulin resistance conditions …”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9][10][11][12][13] PKR is activated by cytokines and various other forms of stress signals, plays a critical role in pathogen sensing, and acts as a regulator of inflammation, insulin resistance, and glucose balance. [7][8][9][10][11][12][13] PKR is an important component of the innate immunity, antiviral, and apoptotic pathways. Recently, palmitate was reported to be involved in apoptosis by binding near to the ATP binding site for reducing the autophosphorylation of PKR at the Thr451 and Thr469.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of protein kinase R protects against palmitic acid–induced inflammation, oxidative stress, and apoptosis through the JNK/NF‐kB/NLRP3 pathway in cultured H9C2 cardiomyocytes

J of Cellular Biochemistry

Bhat

Udumula

et al. 2018

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Background and Purpose: Double-stranded RNA-dependent protein kinase (PKR) is a critical regulator of apoptosis, oxidative stress, and inflammation under hyperlipidemic and insulin resistance conditions. Saturated free fatty acids, such as palmitic acid (PA), are known inducers of apoptosis in numerous cell types. However, the underlying molecular mechanism is not fully understood. The aim of the present study was to examine the effect of PA on cultured rat H9C2 cardiac myocytes cells and to investigate the PKR mediated harmful effects of PA in vitro in cultured cardiomyocytes.Experimental Approach: PKR expression was determined by immunofluorescence and immunoblotting. Oxidative stress and apoptosis were determined by flow cytometry and assay kits. The expression of different gene markers of apoptosis, oxidative stress, and inflammation were measured by Western blot analysis and reverse transcription polymerase chain reaction.Key Results: PKR expression, reactive oxygen species levels as well as apoptosis were increased in PA-treated cultured H9C2 cardiomyocytes. The harmful effects of PA were attenuated by a selective PKR inhibitor, C16.Moreover, we observed that upregulation of c-Jun N-terminal kinase (JNK), nuclear factor-kB (NF-kB) and NACHT, LRR and PYD domains-containing protein 3 (NLRP3) pathways is associated with increased expression of interleukin 6 and tumor necrosis factor-α in PA-treated cardiomyocytes and attenuation by a selective PKR inhibitor.Conclusion and Implications: Our study reports, for the first time, that PKRmediated harmful effects of PA in cultured cardiomyocytes via activation of

“…However, macrovascular changes convey a potential risk for the progression of cardiac abnormalities . Obese/overweight individuals or individuals with concomitant hyperglycaemia, hypertension, dyslipidaemia, pathogenic and proinflammatory state are highly susceptible to cardiac complications . In view of multiple CV risk factors beyond hyperglycaemia that are commonly presentable in majority of the T2D patients, a multifactorial approach for combating these CV risk contributors needs to be highlighted.…”

Section: Introductionmentioning

confidence: 99%

SGLT1 inhibition boon or bane for diabetes‐associated cardiomyopathy

Kalra

Fundamemntal Clinical Pharma

Dasari

et al. 2019

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Chronic hyperglycaemia is a peculiar feature of diabetes mellitus (DM). Sequential metabolic abnormalities accompanying glucotoxicity are some of its implications. Glucotoxicity most likely corresponds to the vascular intricacy and metabolic alterations, such as increased oxidation of free fatty acids and reduced glucose oxidation. More than half of those with diabetes also develop cardiac abnormalities due to unknown causes, posing a major threat to the currently available marketed preparations which are being used for treating these cardiac complications. Even though impairment in cardiac functioning is the principal cause of death in individuals with type 2 diabetes (T2D), reducing plasma glucose levels has little effect on cardiovascular disease (CVD) risk. In vitro and in vivo studies have demonstrated that inhibitors of sodium glucose transporter (SGLT) represent a putative therapeutic intervention for these pathological conditions. Several clinical trials have reported the efficacy of SGLT inhibitors as a novel and potent antidiabetic agent which along with its antihyperglycaemic activity possesses the potential of effectively treating its associated cardiac abnormalities. Thus, hereby, the present review highlights the role of SGLT inhibitors as a successful drug candidate for correcting the shifts in deregulation of cardiac energy substrate metabolism together with its role in treating diabetes‐related cardiac perturbations.