Tisp40 prevents cardiac ischemia/reperfusion injury through the hexosamine biosynthetic pathway in male mice

Abstract

The hexosamine biosynthetic pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to facilitate O-linked GlcNAc (O-GlcNAc) protein modifications, and subsequently enhance cell survival under lethal stresses. Transcript induced in spermiogenesis 40 (Tisp40) is an endoplasmic reticulum membrane-resident transcription factor and plays critical roles in cell homeostasis. Here, we show that Tisp40 expression, cleavage and nuclear accumulation are increased by cardiac ischemia/reperfusion (I/R) injury. Global Tisp40 deficiency exacerbates, whereas cardiomyocyte-restricted Tisp40 overexpression ameliorates I/R-induced oxidative stress, apoptosis and acute cardiac injury, and modulates cardiac remodeling and dysfunction following long-term observations in male mice. In addition, overexpression of nuclear Tisp40 is sufficient to attenuate cardiac I/R injury in vivo and in vitro. Mechanistic studies indicate that Tisp40 directly binds to a conserved unfolded protein response element (UPRE) of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) promoter, and subsequently potentiates HBP flux and O-GlcNAc protein modifications. Moreover, we find that I/R-induced upregulation, cleavage and nuclear accumulation of Tisp40 in the heart are mediated by endoplasmic reticulum stress. Our findings identify Tisp40 as a cardiomyocyte-enriched UPR-associated transcription factor, and targeting Tisp40 may develop effective approaches to mitigate cardiac I/R injury.

Taxifolin protects against doxorubicin-induced cardiotoxicity and ferroptosis by adjusting microRNA-200a-mediated Nrf2 signaling pathway

“…3 E and F). Additionally, by detecting ROS and DHE [ 37 , 38 ], we found that TAX inhibited ROS and DHE production ( Fig. 3 G).…”

HINT2 protects against pressure overload‐induced cardiac remodelling through mitochondrial pathways

“…The mRNA extraction and RT‐PCR were done as described in our previous study 21 . In short, TRIzol reagent (Invitrogen, Carlsbad, CA, USA) was used to extract total RNA, while a Transcriptor First Strand cDNA Synthesis Kit (Roche, Basel, Switzerland) was utilized to produce cDNA from the extracted total RNA.…”

“…The mRNA extraction and RT‐PCR were done as described in our previous study. 21 In short, TRIzol reagent (Invitrogen, Carlsbad, CA, USA) was used to extract total RNA, while a Transcriptor First Strand cDNA Synthesis Kit (Roche, Basel, Switzerland) was utilized to produce cDNA from the extracted total RNA. Subsequently, SYBR Green I was used for quantitative RT‐PCR, and the primer sequences for HINT2, β‐actin, natriuretic peptides A (NPPA), natriuretic peptides B (NPPB), myosin‐6 (Myh6), myosin‐7 (Myh7), collagen‐3 (Col III), collagen‐1 (Col I), fibronectin (FN), connective tissue growth factor (CTGF), NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 (Ndufa13), NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11 (Ndufb11), Ndufb7, Ndufa2, Ndufa1, Ndufa3, NADH dehydrogenase [ubiquinone] iron–sulfur protein 7 (Ndufs7), Ndufb8, Ndufb6, Ndufa8 are provided in Table S1 .…”

“…The mRNA extraction and RT-PCR were done as described in our previous study. 21 In short, TRIzol reagent (Invitrogen, Carlsbad, CA, USA) was used to extract total RNA, while a Transcriptor First S1. The mRNA expression was standardized by comparing it to the levels of β-actin.…”

Inhibition of ferroptosis by POLE2 in gastric cancer cells involves the activation of NRF2/GPX4 pathway

“…Reactive oxygen species was measured using a 6‐carboxy‐2′,7′‐dichlorodihydrofluorescein diacetate (H2DCFDA, C2938; Thermo Fisher Scientific) as previously described. 44 , 45 , 46 Briefly, cells were incubated with 5 μmol/L H2DCFDA probe at 37°C for 1 h, and then the fluorescence was measured with an excitation wavelength of 488 nm and emission at 525 nm by a spectrofluorometer. To analyse lipid peroxidation, malondialdehyde (MDA) level was measured using a Lipid Peroxidation Assay Kit (ab118970; Abcam) following the manufacturer's instructions.…”