Biology subjects

Visnagri, A.

Publications and source records attributed to Visnagri, A..

3 recordsLinked to original sources

bioRxiv2026

Redox-activated induction of Warburg-type metabolism in the adult heart

Proliferating cells rewire glucose metabolism away from oxidative ATP production towards glycolysis and anabolic branch pathways (the Warburg effect). In contrast, the contractile function of terminally differentiated cardiomyocytes in the heart critically depends upon mitochondrial ATP generation. Adult cardiomyocytes are largely non-proliferative but undergo hypertrophy in response to increased heart workload. A fundamental question in the field is how cardiac metabolism is modified to balance competing energetic and anabolic demands. We previously reported that the redox-signalling H2O2-generating enzyme, NADPH oxidase 4 (NOX4), facilitates compensated cardiac function in hearts undergoing hypertrophic remodelling. Here, we show that NOX4 induces Warburg-type reprogramming of glucose metabolism in the healthy heart, with increased flux into the pentose phosphate, serine and nucleotide biosynthetic pathways. Using an integrated multiomics approach, we uncover a NOX4-regulated network involving interplay between direct transcriptional activation of metabolic genes via NRF2 [aka NFE2L2] and ATF4 and a broader epigenetic regulation. This reprogramming of glucose intermediary metabolism along with previously reported NOX4-mediated enhancement of fatty acid oxidation may serve to optimally support the dual requirements of increased energy demand and remodelling in the heart. Our findings identify a novel paradigm for redox-regulated Warburg-type metabolic reprogramming in the terminally differentiated heart.

physiology↗

bioRxiv2023

NRF2 activation in the heart induces glucose metabolic reprogramming and mediates cardioprotection via upregulation of the pentose phosphate pathway.

RationaleThe transcription factor NRF2 is well recognized as a master regulator of antioxidant responses and cytoprotective genes. Previous studies showed that NRF2 protects mouse hearts during chronic hemodynamic overload at least in part by reducing oxidative stress. Evidence from other tissues suggests that NRF2 may modulate glucose intermediary metabolism but whether NRF2 has such effects in the heart is unclear. ObjectiveTo investigate the role of NRF2 in regulating glucose intermediary metabolism and cardiac function during disease stress. Methods and ResultsCardiomyocyte-specific Keap1 knockout (csKeap1KO) mice, deficient in the endogenous inhibitor of NRF2, were used as a novel model of constitutively active NRF2 signaling. Targeted metabolomics and isotopomer analysis were employed in studies with 13C6-glucose in csKeap1KO and wild-type (WT) mice. Pharmacological and genetic approaches were utilized in neonatal rat ventricular cardiomyocytes (NRVM) to explore molecular mechanisms. We found that cardiac-specific activation of NRF2 upregulated key enzymes of the Pentose Phosphate Pathway (PPP), redirected glucose metabolism towards the PPP and protected the heart against pressure overload-induced cardiac dysfunction. In vitro, knockdown of Keap1 upregulated PPP enzymes and reduced cell death in NRVM subjected to chronic neurohumoral stimulation. These pro-survival effects were abolished by pharmacological inhibition of the PPP or silencing of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of NRF2 in NRVM increased stress-induced DNA damage which was rescued by supplementing the cells with either NADPH or nucleosides, the two main products of the PPP. Activation of NRF2 also protected the heart against myocardial infarction-induced DNA damage, dysfunction, and adverse remodeling. ConclusionsThese results indicate that NRF2 regulates cardiac metabolic reprogramming by stimulating the diversion of glucose into the PPP, thereby providing cardiac protection during stress by generating NADPH and providing nucleotides to prevent stress-induced DNA damage.

physiology↗

bioRxiv2018

Piezo1 channel agonist mimics high glucose as a stimulator of insulin release

ObjectiveGlucose and hypotonicity induced cell swelling stimulate insulin release from pancreatic {beta}-cells but the mechanisms are poorly understood. Recently, Piezo1 was identified as a mechanically-activated nonselective Ca2+ permeable cationic channel in a range of mammalian cells. As cell swelling induced insulin release could be through stimulation of Ca2+ permeable stretch activated channels, we hypothesised a role for Piezo1 in cell swelling induced insulin release.\n\nMethodsTwo rat {beta}-cell lines (INS-1 and BRIN-BD11) and freshly-isolated mouse pancreatic islets were studied. Intracellular Ca2+ measurements were performed using the fura-2 Ca2+ indicator dye. Piezo1 agonist Yoda1, a competitive antagonist of Yoda1 (Dooku1) and an inactive analogue of Yoda1 (2e) were used as chemical probes. Piezo1 mRNA and insulin secretion were measured by RT-PCR and ELISA respectively.\n\nResultsPiezo1 mRNA was detected in both {beta}-cell lines and mouse islets. Yoda1 evoked Ca2+ entry which was inhibited by Yoda1 antagonist Dooku1 as well as other Piezo1 inhibitors gadolinium and ruthenium red, and not mimicked by 2e. Yoda1, but not 2e, stimulated Dooku1-sensitive insulin release from {beta}-cells and pancreatic islets. Hypotonicity and high glucose increased intracellular Ca2+ and enhanced Yoda1 Ca2+ influx responses. Pre-treatment with ruthenium red significantly reduced hypotonicity induced insulin release from {beta}-cells and pancreatic islets.\n\nConclusionThe data show that Piezo1 channel agonist induces insulin release from {beta}-cell lines and mouse pancreatic islets suggesting a role for Piezo1 in cell swelling induced insulin release. Hence Piezo1 agonists have a potential to be used as enhancers of insulin release.

cell biology↗