Biology subjects

Jourd'heuil, F.

Publications and source records attributed to Jourd'heuil, F..

3 recordsLinked to original sources

bioRxiv2026

Genetic deletion of cytoglobin exacerbates cardiac hypertrophy and inhibits cardiac fibroblast activation independent of changes in blood pressure

Hypertension-mediated left ventricular hypertrophy and cardiac fibrosis often precede heart failure. Recent studies indicate that cytoglobin (Cygb), a globin expressed in the vasculature, increases systemic blood pressure. The present work aims to determine the role of Cygb in angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis in the mouse. MethodsMales and females global Cygb knockout (Cygb-/-), and wildtype (Cygb+/+) mice were treated with Ang II (1.5 {micro}g/kg/day) for two weeks via subcutaneous osmotic minipumps. Cardiac function was assessed through echocardiography, and hearts were analyzed for changes in hypertrophy, fibrosis, and gene expression. Functional studies were also performed in isolated cardiac fibroblasts. ResultsCygb-/- mice from both sexes showed an increase in cardiac hypertrophy over Cygb+/+ mice. Cardiac functions were also depressed in Cygb-/- males with no changes in females. Importantly, genetic deletion of Cygb did not affect systemic blood pressure in mice, at baseline or after Ang II treatment. We established that Cygb was expressed in fibroblasts and pericytes in humans and mice hearts. Finally, we found that Cygb-/- cardiac fibroblast did not upregulate the expression of genes associated with myofibroblasts following treatment with Ang II. This was reversed following expression of human cytoglobin. ConclusionsOur findings indicate that Cygb plays a protective role in the mouse heart during Ang II-induced cardiac stress. This is the first study detailing the function of Cygb in the heart as a regulator of cardiac hypertrophy. This study also reveals a role for Cygb in regulating cardiac fibroblast activation by Ang II. NEW & NOTEWORTHYWe identified cytoglobin as an important globin in cardiac pathophysiology. Genetic deletion of cytoglobin led to exacerbation of angiotensin II-mediated cardiac hypertrophy in the absence of any effect on systemic blood pressure. Cytoglobin is expressed in cardiac fibroblasts and pericytes and is required for cardiac fibroblast activation to myofibroblast. The present study reveals for the first time a role for cytoglobin in regulating angiotensin II signaling.

physiology↗

bioRxiv2023

Nuclear cytoglobin associates with HMGB2 and regulates DNA damage and genome-wide transcriptional output in the vasculature

Identifying novel regulators of vascular smooth muscle cell function is necessary to further understand cardiovascular diseases. We previously identified cytoglobin, a hemoglobin homolog, with myogenic and cytoprotective roles in the vasculature. The specific mechanism of action of cytoglobin is unclear but does not seem to be related to oxygen transport or storage like hemoglobin. Herein, transcriptomic profiling of injured carotid arteries in cytoglobin global knockout mice revealed that cytoglobin deletion accelerated the loss of contractile genes and increased DNA damage. Overall, we show that cytoglobin is actively translocated into the nucleus of vascular smooth muscle cells through a redox signal driven by NOX4. We demonstrate that nuclear cytoglobin heterodimerizes with the non-histone chromatin structural protein HMGB2. Our results are consistent with a previously unknown function by which a non-erythrocytic hemoglobin inhibits DNA damage and regulates gene programs in the vasculature by modulating the genome-wide binding of HMGB2.

cell biology↗

bioRxiv2022

DMT1 bridges endosomes and mitochondria to modulate mitochondrial iron translocation

Transient "kiss-and-run" endosome-mitochondria interactions can mediate mitochondrial iron translocation (MIT) but the associated mechanisms are still elusive. We show that Divalent Metal Transporter 1 (DMT1) modulates MIT via endosome-mitochondria interactions in invasive MDA-MB-231, but not in non-invasive T47D breast cancer cells. CRISPR/Cas9-based DMT1 knockout (KO) stable cells were used to demonstrate that DMT1 regulates MIT, endosomal speed, and labile iron pool (LIP) levels only in MDA-MB-231. DMT1 silencing increases PINK1/Parkin mitophagy markers, the autophagy marker LC3B, as well as mitochondrial ferritin in MDA-MB-231, but not in T47D. Strikingly, re-expression of DMT1 in MDA-MB-231 DMT KO cells rescues all protein levels evaluated. DMT1 silencing decreases Tom20 colocalization with PMPCB, a DMT1 interactor that regulates mitophagy hyperactivation. In MDA-MB-231 both mitochondrial metabolism and invasion were impaired by DMT1 silencing and rescued by DMT1 re-expression. DMT1 acts as a bridge between endosomes and mitochondria to support higher MIT/lower LIP levels, which are necessary for sustaining mitochondrial bioenergetics and invasive cancer cell migration. SummaryCellular iron metabolism is tightly regulated, and cancer cells rely on mitochondrial iron for malignancy. Here, we report that the divalent metal transporter DMT1 serves as a bridge between endosomes and mitochondria regulating mitochondrial iron translocation in breast cancer cells.

cell biology↗