# Innate Immunity and Cardiovascular Function in Sepsis

> **NIH NIH R01** · EAST TENNESSEE STATE UNIVERSITY · 2021 · $333,000

## Abstract

The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory
distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), sepsis syndrome and/or
septic shock and multiple organ dysfunction syndrome (MODS)(1). In the United States ~750,000
patients/year develop sepsis syndrome(2). Cardiovascular dysfunction is a major complication associated
with MODS morbidity and mortality. However, the mechanisms by which cardiovascular dysfunction occurs
during sepsis/septic shock remain unclear. Endothelial cell dysfunction contributes to sepsis-induced MODS
and high mortality. Endothelial cells express pattern recognition receptors (PRRs). PRRs recognize pathogen
associated molecular patterns (PAMPs), initiate innate immune and inflammatory responses, and upregulate
adhesion molecule expression, thus promoting immune cell infiltration and organ injury. Therefore,
preservation of endothelial cell function is an important approach for attenuating sepsis-inducedmorbidity and
mortality. During the last grant period, we discovered a novel role for endothelial specific HSPA12B in the
regulation of endothelial cell function and innate immune response during CLP sepsis. HSPA12B is a newly
discovered member of the HSP70 family. It is predominantly expressed in endothelial cells, and plays an
important role in the induction of angiogenesis. We found that endothelial cell specific deficiency of
HSPA12B (HSPA12B-/-) exacerbates mortality and worsens cardiac function in sepsis. In contrast, transgenic
mice that over express endothelial HSPA12B exhibit significantly improved survival outcome and cardiac
function in endotoxemia. Our findings raise an important question, i.e. how does endothelial HSPA12B have
such a profound effect on the mortality and cardiovascular dysfunction associated with polymicrobial sepsis?
We have made a novel observation that HSPA12B can translocate into the nucleus in endothelial cells. We
also discovered that HSPA12B can be released from endothelial cells and transmitted into macrophages via
exosomes where it downregulates inflammatory cytokine production. Our findings suggest that endothelial
HSPA12B has an important role not only for endothelial cell function but also for inflammatory responses by
immune cells during sepsis. Thus, endothelial HSPA12B could be an important effector that mediates
crosstalk between endothelial cells and immune cells during sepsis. Based on the preliminary data, we
hypothesize that “ endothelial HSPA12B is a novel endogenous effector which protects against sepsis
induced cardiomyopathy by differentially regulating endothelial cell function and innate immune inflammatory
responses”. To test these hypotheses, we propose three specific aims. Specific aim 1. Investigate whether
HSPA12B induced protection against septic cardiomyopathy is mediated via regulation of endothelial
function. Specific aim 2. Determine whether the protection against septic cardiomyo...

## Key facts

- **NIH application ID:** 10166858
- **Project number:** 5R01GM083016-12
- **Recipient organization:** EAST TENNESSEE STATE UNIVERSITY
- **Principal Investigator:** Chuanfu Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $333,000
- **Award type:** 5
- **Project period:** 2009-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166858

## Citation

> US National Institutes of Health, RePORTER application 10166858, Innate Immunity and Cardiovascular Function in Sepsis (5R01GM083016-12). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10166858. Licensed CC0.

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