# Mechanisms of cardiac dysfunction in sepsis

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $272,039

## Abstract

PROJECT SUMMARY
Elderly patients are highly vulnerable to cardiac dysfunction while in sepsis. However, the mechanism
underlying the increased risk of cardiac dysfunction in the elderly is poorly understood. Planned studies in this
project will test the hypothesis that aging-related Klotho deficiency and TLR2 overexpression in the heart
augment the myocardial inflammatory responses to sepsis and thereby exacerbate cardiac dysfunction.
This hypothesis rests on the following novel findings: (1) aging exacerbates the myocardial/systemic
inflammatory responses and cardiac dysfunction caused by either endotoxemia or sepsis; (2) the hyper-
inflammatory phenotype of aging heart is characterized by elevated constitutive inflammation, Klotho deficiency
and TLR2 overexpression; (3) TLR2 has a critical role in mediating the inflammatory responses, cardiac
dysfunction and mortality in old septic mice; (4) recombinant Klotho is capable of suppressing TLR2 expression
in aging heart and improving cardiac function in old septic mice; (5) anti-inflammatory cytokine IL-37 increases
myocardial Klotho levels and is potent in protecting cardiac function in old septic mice.
The major goals of this project are to elucidate the mechanism by which aging exerts an impact on myocardial
expression of Klotho and TLR2, and to determine the role of Klotho deficiency and TLR2 overexpression in the
mechanism underlying myocardial inflammatory responses and cardiac dysfunction caused by sepsis in old
mice. We will pursue the following interrelated Specific Aims: (1) to test the hypothesis that Klotho deficiency
plays an important role in aging-related myocardial hyper-inflammation and cardiac dysfunction in sepsis; (2) to
test the hypothesis that lower Klotho levels in aging heart promote TLR2 expression; (3) to explore the
therapeutic potential of anti-inflammatory cytokine IL-37 for organ protection in sepsis.
The planned studies will provide insights into the mechanisms underlying the hyper-inflammatory responses of
aging heart to infection and offer the basis for developing innovative strategies to protect aging heart against
dysfunction caused by sepsis.

## Key facts

- **NIH application ID:** 9994753
- **Project number:** 5R01GM129641-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** XIANZHONG MENG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $272,039
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994753

## Citation

> US National Institutes of Health, RePORTER application 9994753, Mechanisms of cardiac dysfunction in sepsis (5R01GM129641-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9994753. Licensed CC0.

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