# REGULATION OF MYOCARDIAL PHOSPHOLIPASES AND LIPASES IN DIABETIC MYOCARDIUM

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $762,405

## Abstract

PROJECT SUMMARY/ABSTRACT
Diabetic cardiomyopathy is a complex disorder that emanates from the chronic and excessive use of fatty acids to
fuel contractile function in diabetic myocardium due to the lack of insulin signaling and glucose uptake and
utilization. The nearly exclusive use of fatty acids for fuel in diabetic myocardium results in widespread metabolomic
dysregulation that precipitates multiple deleterious alterations in membrane structure and function. During the
current grant interval, we have utilized enabling mass spectrometric technologies we developed to identify a
plethora of novel signaling molecules in diabetic myocardium which we hypothesize contribute significantly to the
bioenergetic inefficiency and maladaptive signaling in diabetic myocardium. We propose that these novel signaling
molecules contribute to the increased mortality of diabetic patients suffering from acute coronary syndromes leading
to myocardial infarction (MI). Moreover, the consequences of these pathologic alterations in signaling pathways in
diabetic myocardium lead to the poor 5 year prognosis of diabetic patients after MI and include bioenergetic
alterations that precipitate hemodynamic compromise, and promote mitochondrial dysfunction characteristic of
diabetic cardiomyopathy. Lipids serve pleiotropic roles in cell function including substrate for energy production in
myocardium. A primary aspect of diabetic cardiomyopathy is the maladaptive and dysfunctional integration of lipid
metabolism with utilization thereby resulting in the production of toxic signaling molecules. Previously, through
genetic, pharmacologic and chemical biological approaches, we have identified three major phospholipases and
lipases in myocardium iPLA2ß (PNPLA9), iPLA2γ (PNPLA8), and iPLA2ζ (PNPLA2; ATGL) that likely serve as
principal mediators of myocardial hemodynamic dysfunction, electrophysiologic alterations and maladaptive
remodeling in diabetic myocardium. Recently, we demonstrated that iPLA2γ and its downstream signaling
metabolites initiate a transformative signaling pathway which likely underlies many of the multiple deleterious
changes manifest in diabetic myocardium. Accordingly, in Specific Aim 1, we will use our enabling suites of mass
spectrometric technologies to identify the types and amounts of novel signaling molecules produced by this
pathway and identify their functions through a systems biology approach to define their specific roles in the initiation
and propagation of diabetic cardiomyopathy. In Specific Aim 2, we have identified a novel mechanism activating
iPLA2ß. Accordingly, we will identify the role of activated iPLA2ß in mediating the maladaptive production of
signaling metabolites in diabetic myocardium and in diabetic myocardium rendered ischemic. In Specific Aim 3, we
will pursue the dramatic changes in triglyceride molecular species in diabetic myocardium which, after hydrolysis by
iPLA2ζ (PNPLA2; ATGL), likely promote dysfunctional signaling in ...

## Key facts

- **NIH application ID:** 9936060
- **Project number:** 5R01HL118639-08
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** RICHARD W GROSS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $762,405
- **Award type:** 5
- **Project period:** 2013-06-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936060

## Citation

> US National Institutes of Health, RePORTER application 9936060, REGULATION OF MYOCARDIAL PHOSPHOLIPASES AND LIPASES IN DIABETIC MYOCARDIUM (5R01HL118639-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9936060. Licensed CC0.

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