Cardiac myocyte β3-adrenergic receptors prevent myocardial fibrosis by modulating oxidant stress-dependent paracrine signaling

Abstract

Cardiac beta3AR protect from fibrosis in response to haemodynamic stress by modulating nitric oxide and oxidant stress-dependent paracrine signaling to fibroblasts. Specific agonism at beta3AR may offer a new therapeutic modality to prevent cardiac fibrosis.

Rationale and design of a multicentre, randomized, placebo‐controlled trial of mirabegron, a Beta3‐adrenergic receptor agonist on left ventricular mass and diastolic function in patients with structural heart disease Beta3‐left ventricular hypertrophy (Beta3‐LVH)

“…infusions of isoproterenol or angiotensin II, transaortic constriction). The results uniformly showed protection of the transgenic mice from the development of pathological remodelling contrary to the wild‐type controls . Importantly, this was not at the expense of LV function, which remained normal.…”

“…Importantly, β 3 AR also mediate antioxidant effects that, unlike previous therapeutic approaches with guanylyl cyclase stimulators (vericiguat) or PDE5 inhibitors (sildenafil), would protect the NO/cGMP signalling from oxidative degradation and preserve its efficacy in remodelling myocardium with prevailing oxidant stress. This antioxidant effect also contributes to decrease paracrine pro‐fibrotic signalling . This anti‐fibrotic effect is likely to prevent further degradation of LV compliance leading to HFpEF, as fibrosis is a pathogenic component of diastolic dysfunction .…”

“…β 3 AR couples to the nitric oxide (NO)/cGMP pathway, resulting in coronary vasodilatation, and raises cGMP in human myocardium, with a resulting effect on cardiac myocytes that is antipathetic to classical β 1–2 AR positive inotropic effects . In preclinical studies, activation of β 3 AR decreases myocardial hypertrophy and fibrosis in response to neurohormonal or haemodynamic stresses, without compromising LV function . As ample evidence now points to the adverse effects of sustained activation of β 1–2 AR, leading to receptor desensitization/internalization, loss of contractile/frequency reserve, adverse remodelling, calcium overload, and myocyte loss, we reasoned that activation of the functionally antipathetic β 3 AR would protect against such deleterious effects of chronic adrenergic stimulation.…”

“…19,20 In preclinical studies, activation of β 3 AR decreases myocardial hypertrophy and fibrosis in response to neurohormonal or haemodynamic stresses, without compromising LV function. 21,22 As ample evidence now points to the adverse effects of sustained activation of β 1-2 AR, leading to receptor desensitization/internalization, loss of contractile/frequency reserve, adverse remodelling, calcium overload, and myocyte loss, we reasoned that activation of the functionally antipathetic β 3 AR would protect against such deleterious effects of chronic adrenergic stimulation. The trial will test the effect of mirabegron, a β 3 AR-selective agonist that was developed and marketed for clinical use in overactive bladder disease, on LV mass and diastolic function.…”

Cardiac β3‐adrenoceptors—A role in human pathophysiology?

“…In contrast, transgenic overexpression of the human β 3 -adrenoceptor in mice resulted in increased inotropic responses to isoprenaline (Kohout et al, 2001). Independently generated mice with cardiac expression of the human β 3 -adrenoceptor at levels comparable to those in human heart (Hermida et al, 2018) largely confirmed these observations: the β 3 -adrenoceptor agonists CL 316,243 and SR 58,611 had a negative inotropic effect at low concentrations, but these vanished at higher concentrations (Tavernier et al, 2003). While nadolol inhibited the blunting of the negative inotropic effect of high agonist concentrations, bupranolol abolished both of these β 3 -adrenoceptor agonistmediated effects, suggesting that the negative effects were mediated by the β 3 -adrenoceptor, but their blunting by other subtypes.…”