# Right Heart Function in Health and Chronic Disease

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2020 · —

## Abstract

Right ventricular failure (RVF) is a serious clinical problem with a poor prognosis. However, specific treatment
options for RVF are very limited. Recent studies suggest that powerful cardioprotective effects are mediated by
α1-adrenergic receptors, in particular the α1A-subtype (α1A-AR). In the current funding period, we found that
chronic stimulation of α1A-ARs had major beneficial effects on RV function in two mouse models of RVF
induced by pulmonary fibrosis or pulmonary artery constriction (PAC). This renewal project will identify the
mechanisms involved in α1A-AR-mediated reversal of RVF and investigate if the beneficial effects of chronic
α1A-AR stimulation extend to beneficial effects in human cardiac muscle preparations.
This renewal project will build on the following preliminary results from the current funding period:
 · In a model of RVF induced by PAC, RVF was reversed by chronic treatment with a highly specific α1A-
 AR agonist (A61603), at a low dose that did not raise blood pressure.
· The beneficial effect of A61603 treatment involved increased signaling by the pro-survival kinase ERK,
 increased BCL-2 (anti-apoptosis factor that protects mitochondria), increased myocardial ATP levels,
 and decreased levels of reactive oxygen species (ROS), suggesting protective effects on mitochondria.
· RVF was associated with increased abundance of a novel intracellular isoform of matrix-
metalloproteinase-2: N-terminal truncated MMP-2 (NTT-MMP-2). NTT-MMP-2 expression was reported
to be induced by ROS and result in mitochondrial dysfunction, decreased ATP production and further
ROS generation. Our preliminary results show that A61603 treatment reduces NTT-MMP-2 in
 mitochondria, and increased myocardial ATP, suggesting improved mitochondrial function.
· In the PAC model of RVF, chronic A61603 treatment decreased ROS, decreased ROS-mediated
 modification of myofilament proteins and increased myofilament force development. Preliminary studies
using computational modeling suggest that increased myofilament force development is a critical factor
in the improved RV function resulting from A61603 treatment.
· We recently reported that the α1A-AR mediates a robust inotropic response in human RV myocardium
 from heart failure patients and that α1A-AR-ERK signaling is present in failing human myocardium.
 These findings suggest that the α1A-AR is present and functional in failing human RV and might be a
therapeutic target to induce cardioprotective effects in patients with RVF.
 Hypothesis 1. For failing RV, chronic A61603 treatment rescues mitochondrial bioenergetic function,
 resulting in increased ATP levels, reduced ROS generation and increased contraction.
 Hypothesis 2. Rescue of mitochondrial bioenergetic function is mediated by reduced NTT-MMP-2 levels.
 Hypothesis 3. Chronic α1A-AR stimulation is beneficial in human cardiac muscle preparations.
Aim 1. Determine if chronic A61603 treatment of RVF rescues mitochondrial bioenergetic function;
l...

## Key facts

- **NIH application ID:** 9783206
- **Project number:** 2I01BX000740-09
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** Anthony J. BAKER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2011-07-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9783206

## Citation

> US National Institutes of Health, RePORTER application 9783206, Right Heart Function in Health and Chronic Disease (2I01BX000740-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9783206. Licensed CC0.

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