# Calcineurin compartmentation and regulation of pathological cardiac remodeling

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $522,649

## Abstract

The Ca2+/calmodulin-dependent phosphatase calcineurin (CaN, PP2B) is a pleiotropic signaling enzyme
important for the regulation of cardiac hypertrophy. While CaN inhibition will attenuate pathological cardiac
remodeling, therapeutic targeting of CaN is problematic as clinically established CaN inhibitors are
immunosuppressant and as CaN targeting can worsen myocardial injury due to ischemia/reperfusion. In theory,
however, if CaN signaling pathways mediating pathological cardiac hypertrophy could be targeted in isolation, a
new therapeutic paradigm could be established. Two isoforms of CaNA, α and β, are expressed as proteins
equally in the heart, and yet genetic targeting of CaNAβ (PPP3cb) is sufficient to blunt pathological hypertrophy
in mice. We recently discovered that CaNAβ2 is targeted through its unique N-terminal polyproline (PP) domain
to a myocyte compartment organized by the scaffold protein Cdc4-Interacting Protein 4 (CIP4, TRIP10). Imaging
using Forster Resonance Energy Transfer (FRET) reporters revealed that CIP4-bound CaNAβ2 is activated by
G-protein coupled receptor signaling, including angiotensin II, α- and β-adrenergic receptors, but not by pacing
that induces myocyte contraction. Notably, both CIP4 gene targeting and adeno-associated virus-mediated PP-
domain anchoring disruption inhibited cardiac remodeling and improved cardiac function in response to pressure
overload. Thus, CaNAβ PP-dependent anchoring constitutes a novel mechanism for specification of CaN
function, providing an explanation for the specific role of CaNAβ in the cardiac myocyte, as well as for the
important question why hypertrophic CaN signaling is not active in normal contracting myocytes. In this project,
we will test the novel hypothesis that in the cardiac myocyte PP-domain anchoring and CIP4 compartmentation
confer CaNAβ2 action selectively promoting pathological cardiac hypertrophy, thereby comprising a new
therapeutic target for the prevention and/or treatment of heart failure. Specific Aim 1: Localization and
function of the CIP4 signaling compartment. This Aim will define CIP4 localization in the myocyte, study the
relevance of the various CIP4 domains for myocyte hypertrophy, and explore whether CIP4-associated CaNAβ2
acts locally or distally from CIP4 complexes to promote hypertrophy. Specific Aim 2: Regulation of Ca2+ in the
CIP4-CaNAβ2 compartment. Functional independence of a Ca2+ signaling compartment requires mechanisms
for both local influx of Ca2+ and for insulating the compartment against elevations in Ca2+ associated with other
cellular functions. In this Aim, we will define the source of Ca2+ and how this compartment is insulated using live
myocyte imaging. Specific Aim 3: PP-anchored CaNAβ and ischemic heart disease. This aim will test
whether targeting of PP-anchored CaNAβ can attenuate the development of heart failure without worsening
myocyte survival in ischemic heart disease, These Aims will elucidate how PP-domain-mediated anch...

## Key facts

- **NIH application ID:** 10361509
- **Project number:** 5R01HL158052-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Michael Seth Kapiloff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $522,649
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10361509

## Citation

> US National Institutes of Health, RePORTER application 10361509, Calcineurin compartmentation and regulation of pathological cardiac remodeling (5R01HL158052-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10361509. Licensed CC0.

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