α1A‐Subtype Adrenergic Therapy is Beneficial for Failing Right Ventricle (RV)
Authors: Cowley Patrick M , Wang Guanying , Joshi Sunil , Lovett David H , Simpson Paul C , Baker Anthony J 
Published: November 2023

Compared to non‐failing RV, we reported that failing RV had an increased inotropic response to stimulation of α1‐adrenergic receptors (α1‐ARs). Recently, we found that a single subtype (α1A) was responsible. We hypothesized that increased α1A‐subtype signaling is beneficial in RV failure and a potential therapeutic target. Studies in several laboratories suggest that chronic α1A‐subtype stimulation has a beneficial effect on LV function in multiple heart failure models. However, no studies have investigated chronic α1A‐subtype stimulation in the setting of RV failure.

Goal

Determine if α1A‐subtype adrenergic therapy is beneficial for failing RV.

Methods

We used tracheal instillation of the fibrogenic antibiotic bleomycin in mice to induce pulmonary fibrosis, pulmonary hypertension, and RV failure within 2 wk. Mice were treated concurrently using osmotic mini‐pump infusion with either a low dose of the α1A‐subtype agonist A61603 (10ng/kg/day) or saline (vehicle controls). We assessed multiple readouts of cell injury in failing RV and determined if these were improved by A61603 therapy.

Results

Multiple readouts of cell injury in failing RV myocardium were markedly attenuated by A61603 therapy. Specifically, the Table summarizes that the level of serum troponin I (TnI) was significantly increased in the bleomycin RV failure model and this increase was prevented by A61603 therapy. Myofilament force development was significantly reduced in failing RV, and this decrease was prevented by A61603 therapy. Two isoforms of matrixmetalloproteinase‐2 (MMP‐2), which are associated with cell injury, were increased in failing RV, and these increases were prevented by A61603 therapy. Finally, bleomycin‐induced pulmonary fibrosis was associated with markedly increased lung weight, and this increase was not abolished by A61603 therapy, suggesting that the beneficial effect of A61603 therapy on the RV did not occur via a beneficial effect on the bleomycin model of lung injury. Preliminary studies suggest that the beneficial effect of A61603 therapy involves a reduction in the level of oxidative stress.

Conclusion

Chronic therapy with the α1A‐subtype‐specific agonist A61603 resulted in decreased cellular injury in a model of RV failure. The α1A‐subtype is a potential therapeutic target to treat RV failure.

Support or Funding Information

Supported by Department of Veterans Affairs Merit Review Awards I01BX000740 (AJB), I01BX000593 (DHL), National Heart, Lung and Blood Institute Grant HL31113 (PCS) and an American Heart Association Grant‐in‐Aid (AJB).

A61603 Treatment Reduced Markers of Cell Injury in Bleomycin‐Induced RV Failure

Non‐failing
Bleomycin
Bleomycin +A61603

Serum Tnl (ng/ml)
5.6 ± 0.8
11.7 ± 0.6***
6.7 ± 0.7

Fmax (nN/mm2)
88 ± 3
64 ± 2***
79 ± 2

FL‐MMP‐2
1
9.8 ± 1.8*
3.9 ± 0.8

NTT‐MMP‐2
1
6.2 ± 1*
2.2 ± 1

Lung wt. /body wt. (mg/g)
7.2 ± 0.2
13 ± 0.3***
12.9 ± 0.4***

Significant differences compared to non‐failing:

P < 0.001;

P < 0.05.