# Pathogenesis of Cardiopulmonary Fibrosis Associated with Heart Failure in the Elderly

> **NIH NIH R01** · TUFTS MEDICAL CENTER · 2022 · $704,311

## Abstract

Project Summary/Abstract
Aging-related adverse remodeling in cardiac and pulmonary tissues is increasingly recognized in patients with
heart failure with preserved ejection fraction (HFpEF). HFpEF is associated with the development of fibrosis
and decreased compliance (increased stiffness) of these vital structures. In turn, this structural rigidity results
in increased work load and eventual HF with poor clinical outcomes. Little is known about the basic
mechanism by which this tissue stiffness occurs. We have found evidence for elevation of expression and
activity of tissue transglutaminase (TG2) in age-dependent pathologies including senescence and chronic
cardiac pressure overload, occurring with enhanced glycolytic metabolism. Since TG2 is known to participate
in protein cross-linking and stimulation of fibrogenesis, we hypothesize that this aging-mediated enhancement
of TG2 through glycolytic stress sets in motion a variety of biologic events, including fibroblast activation and
extracellular matrix protein collagen deposition and cross-linking that lead to development of tissue stiffness in
experimental HFpEF. We wish to explore this novel hypothesis with the idea that intervention of TG2 activity
may provide a new therapeutic approach for age-related HFpEF. In Specific Aim 1, we will utilize senescent
and control fibroblasts in vitro to directly explore the influence of aging-related biologic pathways on
mechanistic relationships between glycolysis, TG2, lysyl oxidase (LOX), matrix protein alteration and cell
signaling and physiologic function. Expected outcome: These in vitro studies will advance our understanding
about upstream aging-related mechanisms that mediate TG2 induction and associated downstream signaling
pathways. In Specific Aim 2, we will use wild-type mice and a senescent-accelerated mouse (SAM) model
including prone (SAMP8) and resistant (SAMR1) strains with or without pressure-overload of the cardiac left
ventricle (constriction of the aorta) to assess aging-related in vivo molecular and physiologic responses of
cardiac and pulmonary tissue remodeling, fibrosis and stiffness. Additionally, we will use these senescent
mouse models to assess the influence of ERW1041E, a TG2 inhibitor, on these pathophysiological responses
to test validation of TG2 as a significant mediator of aging-dependent tissue fibrosis and HFpEF. We will
determine the extent of TG2-mediated collagen accumulation and LOX-mediated collagen oxidation in cardiac
and pulmonary tissues in these mice with use of novel in vivo imaging techniques and further relate them to
fibrogenic progression and remission. Further, TG2-mediated matrix protein crosslinking will be assessed
using a non-invasive bioassay. Expected outcome: We hope that these studies will provide new insights into
mechanisms by which tissue fibrosis and stiffness occur in aging hearts and lungs. Significance: The results of
our studies may lead to similar techniques in humans to assess the pres...

## Key facts

- **NIH application ID:** 10319601
- **Project number:** 5R01AG064064-03
- **Recipient organization:** TUFTS MEDICAL CENTER
- **Principal Investigator:** Krishna C Penumatsa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $704,311
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10319601

## Citation

> US National Institutes of Health, RePORTER application 10319601, Pathogenesis of Cardiopulmonary Fibrosis Associated with Heart Failure in the Elderly (5R01AG064064-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10319601. Licensed CC0.

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