# A Role of PKG1a and Inhibitors of cGMP Phosphodiesterase in Post MI VT in Mouse Models for Type II Diabetes and Metabolic Syndrome

> **NIH NIH R01** · TUFTS MEDICAL CENTER · 2020 · $663,296

## Abstract

Project Summary
The current application proposes to investigate the novel mechanisms through which cGMP and the cGMP-
dependent protein kinase I (PKGI) maintain Ca homeostasis and oppose ventricular tachycardia (VT) in the
diabetic heart in the setting of acute MI. Diabetes mellitus (DM) is associated with an increase in sudden cardiac
death (SCD), but the molecular and cellular mechanisms of arrhythmogenesis in DM remain incompletely
understood. T-Wave alternans (TWA) is a rate dependent beat-to-beat fluctuation on the surface EKG that has
been associated with life threatening ventricular arrhythmias. T-wave alternans has been described in patients
with Type II DM, and hyperactivity of GSK3β has been implicated in secondary effects of DMII, but little is known
regarding the mechanism of alternans and its specific role in the pathogenesis of VT in patients, or in mouse
models for Type II DM. Inducibility of VT in response to programmed ventricular stimulation has been used to
identify patients whose hearts are predisposed to the development of VT. Preliminary data in the current
application identify significant inducibility of VT and of TWA in two separate models: the Db/Db mouse model of
DMII, and in the High Fat High Sucrose (HFHS) fed mouse model of insulin insensitivity. More importantly, we
have demonstrated that these mice develop severe spontaneous arrhythmias following myocardial infarction
(MI). We have observed that the intracellular signaling molecule cGMP is decreased in both of these above
models. Further, genetic disruption of the primary cardiovascular cGMP effector, Protein Kinase G Iα (PKGIα)
leads to T-wave alternans and highly inducible VT, providing direct evidence that this kinase plays a role in the
pathogenesis of VT in vivo. Rescue experiments demonstrate that augmentation of cGMP with the cGMP-
selective phosphodiesterase 5 inhibitor sildenafil abolishes VT and TWA in the Db/Db and HFHS mice, while the
GSK3β inhibitor TWS-119 attenuates VT. Based on these and published data implicating GSK3β as a PKG1α
substrate, the current application proposes to test the hypothesis that PKGIα opposes both inducible and
spontaneous post MI VT in the diabetic heart through the regulation of GSK3β activity. We propose 3 Specific
Aims: 1) Determine the anti-arrhythmic effects of PKGI augmentation in the DMII heart by PDE inhibitors and
Guanylate cyclase activators; 2) Determine the physiologic mechanisms by which PKGIα dysfunction
predisposes to inducible and post MI VT and alternans via an effect on Ca homeostasis; 3) Determine the
downstream signaling mechanisms through which disruption of cGMP-PKG signaling promotes VT in the DMII
heart. The data generated from these studies will determine the role of PKGIα signaling in the regulation of VT
in the DM II heart and has the potential to identify pharmacologic modulation of PKGI as a novel anti-arrhythmic
strategy in patients with DM.

## Key facts

- **NIH application ID:** 10035716
- **Project number:** 1R01HL153433-01
- **Recipient organization:** TUFTS MEDICAL CENTER
- **Principal Investigator:** Jonas Bernard Galper
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $663,296
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10035716

## Citation

> US National Institutes of Health, RePORTER application 10035716, A Role of PKG1a and Inhibitors of cGMP Phosphodiesterase in Post MI VT in Mouse Models for Type II Diabetes and Metabolic Syndrome (1R01HL153433-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10035716. Licensed CC0.

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