# Mitochondrial CAMKII in smooth muscle as key regulator of hypertension and vascular remodeling

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2020 · —

## Abstract

Despite multiple initiatives in the VA healthcare system, at least 30% of the estimated three million Veterans
with hypertension do not reach the current target blood pressure (BP). Hypertension induces pathological
remodeling of the vascular wall, leading to further increases in BP and end organ dysfunction. These effects
are linked to 5,000 annual deaths among Veterans. Emerging data suggest that mitochondrial ROS
production is a common denominator in hypertension, but mechanistic concepts of how mitochondrial
function in VSMC drives hypertension and remodeling are missing. Our group has made significant
contributions to unraveling the function of the multifunctional Ca2+/calmodulin-dependent kinase II (CaMKII)
in the vasculature in vivo and defined previously unrecognized pathways by which CaMKII controls VSMC
Ca2+ handling, remodeling and BP. Of note, CaMKII is present in mitochondria and believed to control
mitochondrial matrix Ca2+ influx via the mitochondrial Ca2+ uniporter. We recently made the novel discovery
that inhibition of CaMKII in VSMC is sufficient to block mitochondrial ROS production and prevent
Angiotensin-II (Ang-II) hypertension. Our long-term goal is to help develop selective CaMKII inhibitors that
can be used clinically for the treatment of hypertension. As a next step toward this goal, the objective of this
application is to delineate the function of CaMKII in hypertension-induced mitochondrial dysfunction. Here we
propose to test the novel and innovative hypothesis that CaMKII contributes to a ROS-generating, pro-
hypertensive feed forward circuit in vascular smooth muscle by actions in mitochondria. We have developed
new genetic mouse models where we can conditionally and selectively control mitochondrial CaMKII in
VSMC, which will be used to test the following three specific aims: 1) Dissect the molecular pathways by
which mitoCaMKII controls mitochondrial function and mitoROS production in VSMC. 2) Dissect the
mechanisms by which mitoCaMKII inhibition in VSMC protects against vascular wall remodeling and
hypertension by Ang-II. 3) Establish the therapeutic potential of mitoCaMKII inhibition in a model of chronic
hypertension. Aim 1 will provide the cellular mechanisms through which CaMKII controls mitochondrial
function. Data from aim 2 will determine pathways by which mitochondrial CaMKII in VSMC drives BP
increases through mitochondrial ROS, whereas aim 3 will directly test whether mitochondrial CaMKII
inhibition in VSMC can be used as treatment in hypertension. The approach is innovative because of its use
of novel in vivo models and specific tools to dissect mitochondrial function. The proposed research is
significant because it is expected to advance the field by defining a novel molecular target for
antihypertensive therapy. Ultimately, such knowledge may allow for the development of new therapeutic
strategies in hypertension that will benefits our Veterans.

## Key facts

- **NIH application ID:** 9932896
- **Project number:** 5I01BX000163-11
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Isabella Maria Grumbach
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2010-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932896

## Citation

> US National Institutes of Health, RePORTER application 9932896, Mitochondrial CAMKII in smooth muscle as key regulator of hypertension and vascular remodeling (5I01BX000163-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932896. Licensed CC0.

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