# Role of endothelial cell senescence in age-related cardiomyopathy

> **NIH NIH R21** · EAST TENNESSEE STATE UNIVERSITY · 2024 · $187,500

## Abstract

Abstract
 Age is a major risk factor for cardiovascular associated diseases which are leading causes of death
globally. Accordingly, 80% of all cardiovascular deaths occurred in patients aged 65 and over. Endothelial cell
senescence, characterized by cell cycle arrest and a senescence-associated secretory phenotype (SASP), is a
major contributor to age related cardiovascular dysfunction. However, the mechanism by which endothelial
cells are subjected to senescence is still unclear.
 We have recently made novel findings that endothelial cell HSPA12B deficient (eHSPA12B-/-) mice exhibit
cardiac endothelial cell senescence accompanied by severe cardiac hypertrophy, fibrosis, and persistent
inflammation when compared with age- and gender-matched WT controls. Our findings suggest that senescent
endothelial cells play an important role in the regulation of cardiac hypertrophy and fibroblast activation and
that endothelial cell HSPA12B limits senescence of endothelial cells. Therefore, understanding the
mechanisms by which HSPA12B regulates endothelial cell senescence would be important for seeking an
approach to prevent or reverse senescent endothelial cells, thus reducing age-related cardiovascular disease.
 To elucidate how HSPA12B limits senescence of endothelial cells, we examined the effect of HSPA12B on
ATF6 (Activating transcription factor 6) transcriptional activity and its target gene MANF (Mesencephalic
Astrocyte Derived Neurotrophic Factor) expression. ATF6 is an important transcriptional factor that regulates
the expression of genes involved in proper protein folding and cellular senescence. MANF is an evolutionarily
conserved protective modulator for the maintenance of tissue immune and metabolic homeostasis.
Interestingly, we observed that HSPA12B is critical for sustaining ATF6 transcriptional activity and MANF
expression. The data suggest that ATF6 and MANF may be involved in the HSPA12B mediated protective
effect on endothelial cell senescence.
 To investigate how endothelial cell senescence contributes to cardiac hypertrophy, we examined cardiac
mitochondrial glucose oxidation (MGO) which is one of the major contributors to myocardial energy production.
Compromised mitochondrial glucose oxidation leads to the development of cardiac hypertrophy and eventually
heart failure. We observed that eHSPA12B-/- resulted in decreased Acetyl-CoA and increased lactate
accumulation. The data indicate that eHSPA12B-/- impairs cardiac mitochondrial glucose oxidation. Our
observation also suggests that senescent endothelial cells induce cardiac hypertrophy via impairment of
cardiac myocyte MGO (mitochondrial glucose oxidation).
 To address how endothelial cell senescence impairs cardiac MGO, we induced endothelial cell senescence
by ETO (etoposide), collected the medium as the senescent conditioned medium (SCM), and treated adult
cardiac myocytes with the SCM. We observed that SCM promotes metabolic reprogramming from glucose
oxidation to glycolysis i...

## Key facts

- **NIH application ID:** 10910161
- **Project number:** 5R21AG083408-02
- **Recipient organization:** EAST TENNESSEE STATE UNIVERSITY
- **Principal Investigator:** Xiaohui Wang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $187,500
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10910161

## Citation

> US National Institutes of Health, RePORTER application 10910161, Role of endothelial cell senescence in age-related cardiomyopathy (5R21AG083408-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10910161. Licensed CC0.

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