Adrenergic Receptor Blockade Reverses Right Heart Remodeling and Dysfunction in Pulmonary Hypertensive Rats

Bogaard, Harm Jan; Natarajan, Ramesh; Mizuno, Shiro; Abbate, Antonio; Chang, P.; Chau, Vinh Q.; Hoke, Nicholas N; Kraskauskas, Donatas; Kasper, Michael; Salloum, Fadi N.; Voelkel, Norbert F.

doi:10.1164/rccm.201003-0335oc

Cited by 264 publications

(244 citation statements)

References 56 publications

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“…We have reported that this right ventricle (RV) capillary rarefaction is associated with a decreased myocardial expression of VEGF-A. 35 Now we show that the expression of the VEGF-B splice variant [36][37][38] is likewise decreased in the tissues of failing rat RVs, further supporting the hypothesis that loss of expression of angiogenesis factors can explain the capillary rarefaction 35,39 in failing RVs. 34 …”

Section: Introductionsupporting

confidence: 60%

“…We found a significant reduction in the expressed VEGF-A protein, confirming previous results. 35 A new finding was a reduction in the expressed VEGF-B and VEGF-D proteins, which was not shared by the RV tissues obtained from chronically hypoxic rats, while the expression of VEGF-C trended toward a decrease in the RV tissue samples from SuHx rats without reaching statistical significance ( Fig. 2A-2E ).…”

Section: Survey Of Expressed Vegf Isoforms and Vegf Receptors In Lungmentioning

confidence: 84%

“…RV/LVþS: ratio of right ventricular weight to left ventricular plus septal weight; BALT: bronchus-associated lymphoid tissue. the decreased expression of the ligand proteins VEGF-A, 35 VEGF-B, and perhaps VEGF-D and VEGF-C, together with high circulating levels of the antiangiogenic sFlt-1, could all account for the capillary rarefaction of the failing SuHx rat RV and the metabolic remodeling of the RV tissue. 34 Table 2 lists the RV and lung tissue VEGF isoform expression changes.…”

Section: Discussionmentioning

confidence: 99%

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Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

et al. 2015

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The mechanisms involved in the development of severe angioobliterative pulmonary arterial hypertension (PAH) are multicellular and complex. Many of the features of human severe PAH, including angioobliteration, lung perivascular inflammation, and right heart failure, are reproduced in the Sugen 5416/ chronic hypoxia (SuHx) rat model. Here we address, at first glance, the confusing and paradoxical aspect of the model, namely, that treatment of rats with the antiangiogenic vascular endothelial growth factor (VEGF) receptor 1 and 2 kinase inhibitor, Sugen 5416, when combined with chronic hypoxia, causes angioproliferative pulmonary vascular disease. We postulated that signaling through the unblocked VEGF receptor VEGFR3 (or flt4) could account for some of the pulmonary arteriolar lumen-occluding cell growth. We also considered that Sugen 5416-induced VEGFR1 and VEGFR2 blockade could alter the expression pattern of VEGF isoform proteins. Indeed, in the lungs of SuHx rats we found increased expression of the ligand proteins VEGF-C and VEGF-D as well as enhanced expression of the VEGFR3 protein. In contrast, in the failing right ventricle of SuHx rats there was a profound decrease in the expression of VEGF-B and VEGF-D in addition to the previously described reduction in VEGF-A expression. MAZ51, an inhibitor of VEGFR3 phosphorylation and VEGFR3 signaling, largely prevented the development of angioobliteration in the SuHx model; however, obliterated vessels did not reopen when animals with established PAH were treated with the VEGFR3 inhibitor. Part of the mechanism of vasoobliteration in the SuHx model occurs via VEGFR3. VEGFR1/VEGFR2 inhibition can be initially antiangiogenic by inducing lung vessel endothelial cell apoptosis; however, it can be subsequently angiogenic via VEGF-C and VEGF-D signaling through VEGFR3.

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Section: Introductionsupporting

confidence: 60%

Section: Survey Of Expressed Vegf Isoforms and Vegf Receptors In Lungmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

et al. 2015

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“…However, in the experimental setting there have been reports of drug-induced improvement of chronic RVF that did not affect the lung circulation. Bogaard et al 18 showed that treatment with the nonselective adrenergic receptor blocker carvedilol improved RV function and exercise tolerance. However, the exact mechanism whereby carvedilol treatment improved the function of the failing RV remains to be determined.…”

Section: The Lung Circulation-rv Axis: Implications For Future Therapiesmentioning

confidence: 99%

The Need to Recognize the Pulmonary Circulation and the Right Ventricle as an Integrated Functional Unit: Facts and Hypotheses (2013 Grover Conference series)

2015

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For many patients with severe pulmonary arterial hypertension, heart failure-and, in particular, right heart failure-is the final chapter of their chronic illness. Targeted therapy for pulmonary hypertension is effective only if the right ventricular ejection fraction is maintained or improved. Because improvement of right heart function and reversal of right heart failure are treatment goals, it is important to investigate the cellular and molecular mechanisms that cause right heart failure. Here, we propose that right ventricular capillary rarefaction is an important hallmark of right heart failure and consider that the "sick lung circulation" and the pressure-overloaded right ventricle constitute a functional unit.

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“…11 In addition, in PAH animal models β-blockers clearly have beneficial effects. [42][43][44] Why, then, has there not been an attempt to develop an antiadrenergic therapeutic strategy in PAH, where the status of the RV function is a major Figure 6. Chamber-specific norepinephrine (NE) and neuropeptide Y (NPY) depletion in failing right ventricles (RVs) from patients with pulmonary arterial hypertension (PAH).…”

Section: Could An Antiadrenergic Treatment Be Effective In Rvf Due Tomentioning

confidence: 99%

The Adrenergic System in Pulmonary Arterial Hypertension: Bench to Bedside (2013 Grover Conference Series)

Bristow

Quaife

2015

Pulm. circ.

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In heart failure with reduced left ventricular ejection fraction (HFrEF), adrenergic activation is a key compensatory mechanism that is a major contributor to progressive ventricular remodeling and worsening of heart failure. Targeting the increased adrenergic activation with β-adrenergic receptor blocking agents has led to the development of arguably the single most effective drug therapy for HFrEF. The pressure-overloaded and ultimately remodeled/failing right ventricle (RV) in pulmonary arterial hypertension (PAH) is also adrenergically activated, which raises the issue of whether an antiadrenergic strategy could be effectively employed in this setting. Anecdotal experience suggests that it will be challenging to administer an antiadrenergic treatment such as a β-blocking agent to patients with established moderate-severe PAH. However, the same types of data and commentary were prevalent early in the development of β-blockade for HFrEF treatment. In addition, in HFrEF approaches have been developed for delivering β-blocker therapy to patients who have extremely advanced heart failure, and these general principles could be applied to RV failure in PAH. This review examines the role played by adrenergic activation in the RV faced with PAH, contrasts PAH-RV remodeling with left ventricle remodeling in settings of sustained increases in afterload, and suggests a possible approach for safely delivering an antiadrenergic treatment to patients with RV dysfunction due to moderate-severe PAH.

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Adrenergic Receptor Blockade Reverses Right Heart Remodeling and Dysfunction in Pulmonary Hypertensive Rats

Abstract: Adrenergic receptor blockade reverses RV remodeling and improves RV function in experimental pulmonary hypertension. Beta-adrenergic receptor blockers are not recommended in humans with PAH before their safety and efficacy are assessed in well-designed clinical trials.

Cited by 264 publications

References 56 publications

Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

The Need to Recognize the Pulmonary Circulation and the Right Ventricle as an Integrated Functional Unit: Facts and Hypotheses (2013 Grover Conference series)

The Adrenergic System in Pulmonary Arterial Hypertension: Bench to Bedside (2013 Grover Conference Series)

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