Tisp40 prevents cardiac ischemia/reperfusion injury through the hexosamine biosynthetic pathway in male mice.
Xin ZhangCan HuZhen-Guo MaMin HuXiao-Pin YuanYu-Pei YuanSha-Sha WangChun-Yan KongTeng TengQi-Zhu TangPublished in: Nature communications (2023)
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.
Keyphrases
- transcription factor
- endoplasmic reticulum stress
- left ventricular
- dna binding
- ischemia reperfusion injury
- cell proliferation
- oxidative stress
- binding protein
- high glucose
- gene expression
- induced apoptosis
- stem cells
- poor prognosis
- diabetic rats
- mouse model
- single cell
- long non coding rna
- endothelial cells
- quality improvement
- bone marrow
- liver failure
- small molecule
- intensive care unit
- smoking cessation
- pi k akt