Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment

Abstract

ABSTRACT/SUMMARYOne million patients with congenital heart disease (CHD) live in the US. They have a lifelong risk of developing heart failure. Current concepts do not sufficiently address mechanisms of heart failure development specifically for these patients. We show that cardiomyocyte cytokinesis failure is increased in tetralogy of Fallot with pulmonary stenosis (ToF/PS), a common form of CHD. Labeling of a ToF/PS baby with isotope-tagged thymidine showed cytokinesis failure after birth. We used single-cell transcriptional profiling to discover that the underlying mechanism is repression of the cytokinesis gene ECT2, and show that this is downstream of β-adrenergic receptors (β-AR). Inactivation of the β-AR genes and administration of the β-blocker propranolol increased cardiomyocyte division in neonatal mice, which increased the endowment and conferred benefit after myocardial infarction in adults. Propranolol enabled the division of ToF/PS cardiomyocytes. These results suggest that β-blockers should be evaluated for increasing cardiomyocyte division in patients with ToF/PS and other types of CHD.

Transcriptional Regulation of Postnatal Cardiomyocyte Maturation and Regeneration

“…In mammals, evidence suggests that the predominantly mononucleated and diploid state of embryonic/fetal cardiomyocytes is essential for the high proliferation rates observed in these hearts [ 13 , 20 , 21 , 22 , 23 ]. During postnatal cardiomyocyte cell cycle arrest, karyokinesis (nuclear division) in the absence of cytokinesis (cell division), also known as endoreplication, results in predominantly binucleated cardiomyocytes in a post-mitotic quiescent state within 10 days after birth in rodents ( Figure 1 A) [ 13 , 21 , 24 , 25 ].…”

“…Direct perturbation of cytokinesis in proliferating cardiomyocytes leads to loss of regenerative potential in both zebrafish and neonatal mice, supporting a causative role [ 13 , 26 ]. Cardiomyocyte polyploidization also contributes to the injury response in adult cardiomyocytes, which undergo maladaptive multinucleation or increased nuclear polyploidization in disease/injury conditions [ 22 ]. Thus, cardiomyocyte polyploidization may be both a consequence of, and directly responsible for, the transition from a fetal-like proliferative state to a post-mitotic terminally-mature state.…”

Lamin B2 Levels Regulate Polyploidization of Cardiomyocyte Nuclei and Myocardial Regeneration

“…Cardiomyocytes can be mono-, bi-, or multi-nucleated, and their nuclei can become polyploid. Current research in cardiomyocyte proliferation focuses on understanding the block at cell-cycle entry and the mechanisms inhibiting the completion of cytokinesis (Soonpaa et al, 1996;Liu et al, 2019). However, the existence of polyploid nuclei in mono-and binucleated cardiomyocytes indicates that, besides the cell-cycle blocks at entry and cytokinesis, additional cell-cycle mechanisms exist that generate polyploid nuclei.…”

“…Studies of various species offer clues about the relationship between nucleation, ploidy, and capacity for proliferation. It is thought that myocardial regeneration requires proliferation of mononucleated cardiomyocytes with diploid nuclei because both observations and experimental studies in various species have shown that increased polyploidy reduces heart regeneration (Gonzá lez-Rosa et al, 2018;Hirose et al, 2019;Liu et al, 2019;Patterson et al, 2017). In mice, the prevalence of cardiomyocytes with polyploid nuclei increases within 3 weeks after birth (Alkass et al, 2015;Walsh et al, 2010).…”

Adrenergic Signaling in Circadian Control of Immunity

“…Signaling through adrenergic receptors reportedly modulates various cellular functions or properties, including (but not limited to) cell cycle and proliferation (91,92), migration (93), and cytokine (94) and antibody (95) production. Although historically, signaling through β-ARs has often been associated with anti-inflammatory outcomes, in more recent years, the ability of β-ARs to mediate context-dependent, pro-and antiinflammatory effects has become more widely appreciated (29,94,96).…”