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ERBB4 activation prevents microvascular dysfunction in a large animal model of hypertensive heart disease
Michiel Rl Tubeeckx1, Tijs Bringmans1,2, Bo Goovaerts1
1Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
Insights
Neuregulin-1 (NRG1) stimulation via ERBB4 activation effectively prevented coronary microvascular dysfunction (CMD) in a hypertensive pig model. This novel approach shows promise for treating cardiovascular diseases linked to CMD.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Physiology
Background:
- Coronary microvascular dysfunction (CMD) is a key factor in cardiovascular diseases with limited therapeutic options.
- Neuregulin-1 (NRG1) signaling through ERBB4 exhibits cardioprotective, anti-inflammatory, and antifibrotic properties in heart failure models.
- Investigating NRG1/ERBB4 activation offers a potential new therapeutic strategy for CMD.
Purpose of the Study:
- To evaluate the efficacy of NRG1/ERBB4 stimulation in mitigating CMD within a hypertensive heart disease model.
- To assess the impact of JK07, an NRG1 fusion protein, on microvascular function and cardiac parameters in pigs with deoxycorticosterone acetate (DOCA)-induced hypertension.
Main Methods:
- Hypertensive heart disease was induced in Aachener minipigs using DOCA pellets for 8 weeks.
- DOCA-treated pigs were randomized to receive weekly infusions of JK07 (NRG1 fusion protein) or a vehicle control.
- Microvascular resistance was quantified using bolus thermodilution; cardiac function and cardiac fibrosis were also assessed.
Main Results:
- DOCA treatment significantly increased microvascular resistance and cardiac dysfunction (dP/dtmax), which were both abrogated by JK07.
- JK07 treatment significantly reduced interstitial left ventricular fibrosis compared to DOCA-only pigs.
- JK07 did not alter myocyte size, capillary density, pericyte coverage, vessel thickness, inflammatory markers, or endothelial activation.
Conclusions:
- ERBB4 activation by JK07 effectively prevents coronary microvascular dysfunction in a DOCA-induced hypertensive pig model.
- JK07 demonstrates potential as a therapeutic agent for CMD associated with hypertensive heart disease.
- The precise mechanisms underlying JK07's protective effects on microvascular resistance require further investigation.
Abstract:
Coronary microvascular dysfunction (CMD) participates in the pathophysiology of multiple cardiovascular diseases, but treatment options are limited. A new treatment option may include V-erb-b avian erythroblastic viral oncogene homology-type 4 (ERBB4) stimulation by neuregulin-1 (NRG1), which has anti-inflammatory, antifibrotic, and cardioprotective effects in models of heart failure. This work assess the effect of NRG1/ERBB4 stimulation on CMD in hypertensive heart disease. Hypertensive heart disease was induced in 12 Aachen minipigs by implantation of deoxycorticosterone acetate (DOCA) pellets for 8 wk and compared with six controls. The DOCA pigs were randomized to a weekly infusion of JK07, a NRG1 fusion protein with improved pharmacokinetic and pharmacodynamic properties, or vehicle. Microvascular resistance was measured using the bolus thermodilution method. DOCA significantly increased microvascular resistance compared with controls (from 14.5 to 19.9 mmHg·s, P = 0.028). This increase was abrogated by JK07 (11.3 mmHg·s, P = 0.018 vs. DOCA). dP/dtmax increased by DOCA compared with controls (from 2,415.5 to 4,455.5 mmHg/s, P = 0.011), which was also abrogated by JK07 (3,107.3 mmHg/s, P = 0.055 vs. DOCA). Interstitial left ventricular fibrosis was significantly lower in JK07-treated pigs compared with DOCA only (2.1 vs. 5.4%, P = 0.026), but without a difference in perivascular fibrosis (P = 0.48). JK07 did not affect myocyte cross-sectional area, capillary density, pericyte coverage, microvascular vessel thickness, inflammatory cytokines, or endothelial activation. ERBB4 activation by JK07 can prevent CMD in a DOCA hypertensive pig model. The exact mechanism of the protective effects of JK07 on microvascular resistance remains elusive however.NEW & NOTEWORTHY CMD is implicated in numerous cardiac diseases, for which only a few therapeutic options are available. Stimulation of the ERBB4/NRG1 pathway has shown beneficial effects in preclinical models of heart failure. JK07 is a selective ERBB4 agonist of interest. JK07 was able to prevent the increase in microvascular resistance in a DOCA-induced hypertensive pig model, as measured by the bolus thermodilution method.
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