Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling

Abstract

Significance In failing hearts, norepinephrine (NE) net release and endothelin-1 (ET1) levels are increased. ET1 receptor antagonists were successfully used in preclinical heart failure (HF) studies, but clinical studies did not show beneficial effects in HF patients. We found that mice lacking endothelin receptor A (ET A ) only in sympathetic neurons but not in cardiomyocytes were protected from the development of HF. Mechanistically, the presynaptic reuptake of NE within the heart was preserved in mice lacking ET A only in sympathetic neurons. These data provide an explanation of why patients in clinical studies do not benefit from ET1 receptor antagonists, because these patients are usually treated with β blockers, which interfere with the mechanism of action identified here.

Induction of cardiomyocyte proliferation and angiogenesis protects neonatal mice from pressure overload–associated maladaptation

“…With regard to nerves, myocardial tissue is innervated to regulate heart function. Cardiac pressure overload in adult mice reduced myocardial nerve density, and a similar pattern is observed in human failing myocardium (49)(50)(51). In contrast, in our regenerative pressure overload model, an increased myocardial axonogenesis was detected, which might promote cardiac contractility (e.g., through the release of norepinephrine) and -on the other hand -promote cardiomyocyte proliferation by secreting factors such as neuregulin-1 (52,53).…”

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

“…1994; Lehmann et al. 2014) and we previously showed that coronary vessels from EC‐MR −/− have attenuated endothelin‐induced vasoconstriction (Mueller et al. 2015).…”

“…1994; Lehmann et al. 2014). Thus, an intriguing possibility is that EC‐MR mediates endothelin‐1‐induced vasoconstriction of coronary vessels in TAC mice through its receptors ETA and ETB in the setting of pressure overload, thereby contributing to impaired coronary blood flow and resulting in systolic dysfunction.…”

Involvement of the metabolic sensor GPR81 in cardiovascular control

“…An alternative possibility is that the ET and adrenergic systems are serially coupled downstream of GPR81 activation (Supplemental Figure 5). In support of this, there is evidence that ET receptor A agonism can enhance adrenergic tone by at least 2 mechanisms: (a) via decreasing the reuptake of norepinephrine by the presynaptic nerve terminals at neuromuscular junctions (41) and (b) by increasing sympathetic tone (42).…”