# Novel Cardioprotective sGC/cGMP Microdomains: Therapeutic Targets in Medically Treated HF

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $496,453

## Abstract

This new early stage investigator R01 proposal explores how current guideline directed medical therapy
(GDMT) has completely modified the chronic heart failure (HF) disease state, specifically with regards to
cardiac myocyte signaling via the nitric oxide receptor, soluble guanylyl cyclase (sGC). Although GDMT is
widely used, this modified chronic HF disease state is virtually ignored by preclinical studies. We
discovered that sGC is dysregulated in the hypertrophied, dysfunctional heart and that β-blocker therapy, a
cornerstone of GDMT, alters sGC signaling in the diseased heart in a way that establishes potentially
novel, but latent, cardioprotective cascades. Both pressure- and volume-overload induce re-localization of
sGC away from caveolae, invaginations of the plasmalemma that compartmentalize signal transduction.
Within caveolae, sGC appears protected from oxidation and remains responsive to nitric oxide (NO). In the
hypertrophied, failing heart, sGC that is outside of caveolae becomes oxidized and NO-responsiveness is
blunted. Recently, we discovered that in the face of volume overload stress, β-blockade prevented
myocardial sGC dissociation from caveolae, restored NO-responsiveness of sGC outside of caveolae, and
induced functional coupling between β3 adrenoceptor (β3AR) and sGC within a non-lipid raft membrane
microdomain. Intriguingly, this functional β3AR/sGC coupling was specific to the non-lipid raft microdomain
and was not found in either control nor untreated, hypertrophied hearts. The current proposal applies the
PI's expertise in cardiac sGC signaling, molecular physiology, and clinical HF to the field of cyclic
guanosine monophosphate (cGMP) membrane microdomain signaling. This area has great HF therapeutic
potential given that membrane microdomains act as critical nodes for integrating adrenergic, calcium, and
cyclic nucleotide signaling. This proposal will test our hypothesis that GDMT changes the NO-
responsiveness and functional coupling of sGC within distinct membrane microdomains of cardiac
myocytes, thereby resulting in untapped cardioprotective potential that differs from that in non-failing or
untreated failing hearts. Our preliminary studies suggest that the non-lipid raft microdomain may represent
dyadic junctions. In Aim 1, we will determine the physiological function of plasmalemmal caveolae- vs.
dyadic junction-associated sGC/cGMP signaling in cardiac myocytes. In Aim 2, we will define the effect of
GDMT on myocardial caveolae- vs. dyadic junction associated sGC/cGMP signaling in the pressure
overloaded heart. In Aim 3, we will elucidate how GDMT promotes sGC caveolae-localization and
enhances NO-responsiveness. With our novel cardiac-specific sGC knockout, microdomain-targeted sGC
constructs, and cardioselective AAV9-mediated transgene delivery, we will provide vital mechanistic
evidence for the development of innovative, synergistic therapies for the millions of HF patients already
optimized on GDMT.

## Key facts

- **NIH application ID:** 10183298
- **Project number:** 5R01HL138528-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Emily J Tsai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $496,453
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183298

## Citation

> US National Institutes of Health, RePORTER application 10183298, Novel Cardioprotective sGC/cGMP Microdomains: Therapeutic Targets in Medically Treated HF (5R01HL138528-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10183298. Licensed CC0.

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