# Cardiomyocyte CaM kinase II as a driver of cardiac inflammation and remodeling

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $394,271

## Abstract

ABSTRACT
The heart responds to stress through hypertrophic growth of cardiomyocytes and progresses to heart failure
when stress is sustained. Our previous studies showed that hypertrophy in response to a variety of stimuli
occurs independent of signaling through the calcium/calmodulin dependent protein kinase II (CaMKII) but that
progression to heart failure is attenuated when CaMKII is deleted. Inflammation is a key contributor to the
adverse remodeling associated with heart failure. The long term objective of this proposal is to
demonstrate that CaMKII signaling within cardiomyocytes initiates cardiac inflammation in response to
non-ischemic interventions such as pressure overload (TAC) and that this plays a significant role in
the development of heart failure. Studies proposed in Aim 1 determine if cardiomyocyte localized CaMKII
signaling drives cardiac inflammation using cardiac specific CaMKII knockout mice (CKO) to demonstrate
loss of TAC-induced inflammatory gene expression and inflammasome activation. We determine if these
responses occur specifically in cardiomyocytes by isolation of adult mouse ventricular myocytes from CTL and
CKO mice, and by in situ hybridization and enzymatic assays in tissue sections. CaMKIIC transgenics and
mice with cardiac specific KO of the p65 subunit of NFkB are used to further demonstrate involvement of the
cardiomyocyte in igniting inflammation. Aim 2 asks whether cardiomyocyte CaMKII signaling contributes to
accumulation of inflammatory/immune cells in response to TAC. Work in this aim uses CKO mice to
demonstrate that TAC promotes immune cell responses through cardiomyocyte CaMKII initiated signals.
Studies focus on macrophages and T-cells, using immunohistochemistry and flow cytometry as well as single
cell RNA seq to comprehensively define specific populations of macrophages that accumulate in the heart.
Cardiac specific KOs or knockdown of chemokines/cytokines is used to demonstrate that generation of these
mediators in cardiomyocytes triggers responses of specific immune cell types. Aim 3 determines if blockade
of cardiomyocyte CaMKII-initiated inflammation attenuates adverse remodeling and at what point this
needs to be accomplished. Proposed studies use cardiac specific KO or inhibition of selected inflammatory
mediators to demonstrate that their formation in cardiomyocytes is critical for development of fibrosis and
ventricular dysfunction following TAC. Conditional gene deletion with AAV9 Cre is used to establish the time at
which maximal benefit from CaMKII inhibition is achieved. Our findings should significantly impact future
research since the cardiomyocyte has not previously been considered as a generator of inflammatory signals,
the mechanisms by which inflammatory responses are activated in the absence of “alarmins” has not
heretofore been determined, and the concept that most effective prevention of heart failure development could
be achieved by early cardiomyocyte-targeted anti-inflammat...

## Key facts

- **NIH application ID:** 10073359
- **Project number:** 5R01HL145459-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** JOAN HELLER BROWN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $394,271
- **Award type:** 5
- **Project period:** 2018-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073359

## Citation

> US National Institutes of Health, RePORTER application 10073359, Cardiomyocyte CaM kinase II as a driver of cardiac inflammation and remodeling (5R01HL145459-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073359. Licensed CC0.

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