# Role of miR-222 in pathological hypertrophy and heart failure

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $412,052

## Abstract

Pathological hypertrophy is a common predecessor to heart failure (HF). The heart also grows in
response to exercise but this growth, termed physiological hypertrophy, does not generally lead to adverse
consequences and can even protect the heart against pathological stress. There is a fundamental gap in our
understanding of why cardiac hypertrophy can have such divergent outcomes. Our over-arching hypothesis
is that there are distinct forms of hypertrophy, which may appear superficially similar but have dramatically
different likelihoods of progressing to HF. Our long-term goal is to understand the pathways responsible for
these differences and learn whether they can be exploited therapeutically. The objective of the current
application is to understand the role of the microRNA (miRNA), miR-222, in pathological hypertrophy and HF.
Prior work from the applicant's laboratory identified 16 cardiac miRNAs that were concordantly regulated in
two distinct exercise models. Of these, miR-222, which is also increased in serum of HF patients after
exercise, was necessary for exercise-induced physiological cardiac growth. While miR-222 was not sufficient
to induce cardiac hypertrophy at baseline, it was sufficient to protect against adverse remodeling after
ischemic injury. The role of miR-222 in pathological hypertrophy and HF remains unexplored. Based on
preliminary data presented in this application, we hypothesize that miR-222 – despite being involved in
physiological hypertrophy – paradoxically protects against pathological hypertrophy and the progression to
HF. Moreover, we hypothesize that miR-222 acts as a nodal modulator of physiological versus pathological
genetic programs at least in part through effects on two transcription factors: HMBOX1 and NFATc3. These
central hypotheses will be tested in three integrated Specific Aims. In Aim 1, we will use specific and
effective gain- and loss-of-function models to directly assess the role of miR-222 in pathological hypertrophy
and HF. In Aim 2, a combination of expression profiling and bioinformatic analyses will be used to identify
downstream targets of miR-222 and delineate the mechanisms responsible for its effects in pathological
hypertrophy and HF. In Aim 3, a novel technology termed CombiGEM (Combinatorial Genetics En Masse),
recently developed by our collaborator, Dr. Tim Lu of the MIT Synthetic Biology group, will be used to
investigate the additive or synergistic effects of miRNAs altered in exercised hearts. In vivo studies will be
supported by in vitro investigation of primary cardiomyocytes to elucidate the underlying mechanisms. Our
approach combines innovative hypotheses, technologies, and unique animal models with the complementary
expertise of an outstanding team of collaborating investigators. The proposed research is significant,
because it is expected to advance our understanding of cardiac hypertrophy and HF as well as pathways with
the potential to mitigate these clinically importan...

## Key facts

- **NIH application ID:** 9838783
- **Project number:** 5R01HL135886-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** ANTHONY ROSENZWEIG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,052
- **Award type:** 5
- **Project period:** 2016-12-24 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838783

## Citation

> US National Institutes of Health, RePORTER application 9838783, Role of miR-222 in pathological hypertrophy and heart failure (5R01HL135886-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9838783. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*