# CaMKII signaling in physiology, heart failure and arrhythmias

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2020 · $935,408

## Abstract

Abstract
Heart failure and arrhythmias occur together, are marked by increased reactive oxygen species (ROS), and
are major, unsolved public health problems. Despite this, ROS can be beneficial. However, clear molecular
mechanisms supporting the benefits of ROS are lacking. The potential for ROS to be ‘good and bad’ is called
the ROS paradox. This Outstanding Investigator Award application will propose innovative approaches to
understanding and dissecting healthy from pathological ROS. The goal of this research program is to test a
disruptive concept that ROS activation of the multifunctional calcium and calmodulin kinase II (CaMKII) by
isoform and organelle selective pathways determine physiological and pathological outcomes of ROS
signaling. We discovered that oxidation activates CaMKII (ox-CaMKII, Erickson Cell 2008) and established
that ox-CaMKII, the major CaMKII isoform in heart, causes heart failure and arrhythmias. Our newest studies
extended these findings to show that ox-CaMKII also contributes to asthma. In sharp contrast, our new
preliminary data indicate that ox-CaMKII, an isoform enriched in skeletal muscle, is beneficial and enhances
endurance, insulin sensitivity, lean phenotype, PGC-1, and expression or brain derived neurotrophic factor
(BDNF), a myokine that improves exercise capacity and protects against myocardial injury. Our group
discovered that CaMKII is present in mitochondria and that mitochondrial-targeted inhibition of CaMKII protects
against common forms of myocardial injury associated with high ROS (Joiner Nature 2012). Here we propose
to pursue new models of global (i.e. body-wide) mitochondrial CaMKII inhibition in flies (Drosophila
melanogaster) and mice developed for the proposed OIA studies. Mitochondrial CaMKII inhibited flies have a
prolonged lifespan and resistance to paraquat induced oxidant injury, while mice with global CaMKII inhibition
have reduced mortality in sepsis and increased weight gain. We performed new phosphoproteomic and
metabolic analyses that identified unanticipated mitochondrial CaMKII targets with central roles in metabolism
and ROS production. Our preliminary computational modeling and experimental data suggest that
physiological activation of mitochondrial CaMKII contributes to a beneficial metabolic fight or flight response
that increases ATP; however, sustained and excessive mitochondrial CaMKII activity causes dilated
cardiomyopathy due to loss of complex 1 and ATP deficiency. We and our collaborators will use state of the
art computer modeling, imaging and metabolic studies, and generate a panel of mouse and Drosophila models
using CRISPR/Cas9 to dissect contributions of CaMKII to specific targets relevant to heart failure, arrhythmias
and to health. This research program requires an R35, or similar, mechanism because of its highly innovative
concept that challenges current paradigms in CaMKII and ROS biology, the need to manage large amounts of
data and generate new animals mode...

## Key facts

- **NIH application ID:** 9849806
- **Project number:** 5R35HL140034-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** MARK E ANDERSON
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $935,408
- **Award type:** 5
- **Project period:** 2018-01-22 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849806

## Citation

> US National Institutes of Health, RePORTER application 9849806, CaMKII signaling in physiology, heart failure and arrhythmias (5R35HL140034-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9849806. Licensed CC0.

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