Myofibroblast β2 adrenergic signaling amplifies cardiac hypertrophy in mice

Abstract

Abnormal β-adrenergic signaling plays a central role in human heart failure. In mice, chronic β-adrenergic receptor (βAR) stimulation elicits cardiac hypertrophy. It has been reported that cultured cardiac fibroblasts express βAR; however, the functional in vivo requirement of βAR signaling in cardiac fibroblasts during the development of cardiac hypertrophy remains elusive. β2AR null mice exhibited attenuated hypertrophic responses to chronic βAR stimulation upon continuous infusion of an agonist, isoprenaline (ISO), compared to those in wildtype controls, suggesting that β2AR activation in the heart induces pro-hypertrophic effects in mice. Since β2AR signaling is protective in cardiomyocytes, we focused on β2AR signaling in cardiac myofibroblasts. To determine whether β2AR signaling in myofibroblasts affects cardiac hypertrophy, we generated myofibroblast-specific transgenic mice (TG) with the catalytic subunit of protein kinase A (PKAcα) using Cre-loxP system. Myofibroblast-specific PKAcα overexpression resulted in enhanced heart weight normalized to body weight ratio, associated with an enlargement of cardiomyocytes at 12 weeks of age, indicating that myofibroblast-specific activation of PKA mediates cardiac hypertrophy in mice. Neonatal rat cardiomyocytes stimulated with conditioned media from TG cardiac fibroblasts likewise exhibited significantly more growth than those from controls. Thus, β2AR signaling in myofibroblasts plays a substantial role in ISO-induced cardiac hypertrophy, possibly due to a paracrine effect. β2AR signaling in cardiac myofibroblasts may represent a promising target for development of novel therapies for cardiac hypertrophy.

β2‐adrenergic stimulation induces interleukin‐6 by increasing Arid5a, a stabilizer of mRNA, through cAMP/PKA/CREB pathway in cardiac fibroblasts

“…Many previous reports have demonstrated that IL‐6/IL‐6R signaling induces cardiac remodeling including myocardial hypertrophy 2,23,24 . In addition, we have recently reported that β2AR KO mice ameliorated cardiac hypertrophy and dysfunction induced by continuous ISO stimulation and that constitutive activation of PKA in fibroblasts resulted in cardiac hypertrophy 10 . Taken together with this study, it is possible that β2‐adrenergic stimulation increases IL‐6 release from CFs, contributing to forming cardiac remodeling.…”

“…These results suggested that βAR signaling predominantly upregulated IL‐6. Adult murine CFs mainly expressed β2AR and β3AR, but not β1AR 10 . Thus, we investigated which subtype of βAR was responsible for IL‐6 upregulation in response to ISO (Figure 2A‐C).…”

“…It is widely accepted that β‐adrenergic receptor (βAR) agonist promotes the production of pro‐inflammatory cytokines 8,9 and leads to the onset and/or progression of heart failure. Although adult murine CFs express β2AR and β3AR, 6,10 the signaling pathway downstream of ARs remains to be fully elucidated in CFs. Here, since biological functions of CFs depend on their maturity, we have addressed whether and how βAR stimulation induces the production of pro‐inflammatory cytokines by using adult murine CFs, not neonatal CFs that have been usually used in the previous studies 11,12 …”

Transcription factor old astrocyte specifically induced substance is a novel regulator of kidney fibrosis

“…Finally, to determine the myofibroblast-specific requirement of OASIS in fibrotic kidneys, we generated myofibroblastrestricted OASIS conditional knockout (OASIS cKO) mice using myofibroblast Postn promoter-driven Cre-loxP recombination system ( Figure 9A). 22 First, it was confirmed that the Postn promoter drives Cre recombinase protein expression within cells in renal interstitial fibrotic areas and in glomeruli of OASIS cKO mice Day 7 after UUO ( Figure S9), however, Cre protein is undetectable in WT kidneys. Moreover, the expression of OASIS/Creb3l1 mRNA was dramatically decreased in UUO-kidney and isolated myofibroblasts of OASIS cKO mice following Cre/loxP recombination ( Figure 9B,C).…”

Bone marrow mesenchymal stem cells inhibit cardiac hypertrophy by enhancing FoxO1 transcription

“…Cardiac hypertrophy, characterized by an increase in cell size to maintain cardiac output, can be caused by a variety of pathological stimuli, such as long‐term hypertensive stress, myocardial injury, and adrenergic stimulus overactivation (Imaeda et al, 2019; Shimizu & Minamino, 2016). However, sustained cardiac hypertrophy has been reported as a risk factor for heart failure (Camici et al, 2020), malignant arrhythmia (Liaquat & Makaryus, 2020), sudden death (Shenasa & Shenasa, 2017), and other serious consequences.…”