Single-cell analysis reveals an Angpt4-initiated EPDC-EC-CM cellular coordination cascade during heart regeneration

Mammals exhibit limited heart regeneration ability, which can lead to heart failure after myocardial infarction. In contrast, zebrafish exhibit remarkable cardiac regeneration capacity. Several cell types and signaling pathways have been reported to participate in this process. However, a comprehensive analysis of how different cells and signals interact and coordinate to regulate cardiac regeneration is unavailable. We collected major cardiac cell types from zebrafish and performed high-precision single-cell transcriptome analyses during both development and post-injury regeneration. We revealed the cellular heterogeneity as well as the molecular progress of cardiomyocytes during these processes, and identified a subtype of atrial cardiomyocyte exhibiting a stem-like state which may transdifferentiate into ventricular cardiomyocytes during regeneration. Furthermore, we identified a regeneration-induced cell (RIC) population in the epicardium-derived cells (EPDC), and demonstrated Angiopoietin 4 (Angpt4) as a specific regulator of heart regeneration. angpt4 expression is specifically and transiently activated in RIC, which initiates a signaling cascade from EPDC to endocardium through the Tie2-MAPK pathway, and further induces activation of cathepsin K in cardiomyocytes through RA signaling. Loss of angpt4 leads to defects in scar tissue resolution and cardiomyocyte proliferation, while overexpression of angpt4 accelerates regeneration. Furthermore, we found that ANGPT4 could enhance proliferation of neonatal rat cardiomyocytes, and promote cardiac repair in mice after myocardial infarction, indicating that the function of Angpt4 is conserved in mammals. Our study provides a mechanistic understanding of heart regeneration at single-cell precision, identifies Angpt4 as a key regulator of cardiomyocyte proliferation and regeneration, and offers a novel therapeutic target for improved recovery after human heart injuries.

MG53 is a double-edged sword for human diseases / 生理学报

Mitsugumin 53 (MG53), also named Trim72, is a multi-functional TRIM-family protein, which is abundantly expressed in cardiac and skeletal muscle. It has been shown that MG53 not only plays important physiological roles but also acts as a crucial pathogenic factor of various diseases. First, MG53 preserves cardiac and skeletal muscle integrity via facilitating plasma membrane repair. Second, MG53 is essentially involved in cardiac ischemic preconditioning and postconditioning by activating PI3K-Akt-GSK3β and ERK1/2 cell survival signaling pathways. Moreover, systemic delivery of recombinant MG53 is able to abolish mechanic or ischemia-reperfusion (I/R)-induced injury of multiple organs, including heart, skeletal muscle, lung, kidney and skin. Importantly, MG53 acts as an E3 ligase to mediate the degradation of insulin receptor and insulin receptor substrate-1, and subsequently induces insulin resistance and metabolic diseases such as type-2 diabetes and its cardiovascular complications. In addition, MG53 negatively regulates myogenesis. As a potential therapeutic target of human diseases, multiple facets of MG53 biological function and mechanisms of action should be taken into the consideration to maximize its beneficial effects and minimize potential side-effects. Here in this review, we intend to comprehensively summarize the current progresses on the biological functions of MG53, focusing on its clinical value as a therapeutic target.

Genetic polymorphism of 16 Y-STR loci in Miao, Yao and Dong nationalities of Guangxi population / 法医学杂志

OBJECTIVE@#To investigate the genetic polymorphisms of 16 Y-STR loci and to evaluate the forensic application in Miao, Yao and Dong nationalities of Guangxi population.@*METHODS@#Genotypes of Y-STR loci were tested in a total of 253 healthy unrelated individuals (67 Miao people, 99 Yao people, 87 Dong people) using AmpFlSTR Yfiler PCR amplification kit. Allele frequencies and population genetics parameters of the 16 Y-STR loci were statistically analyzed. The allele frequencies were compared among the three nationalities.@*RESULTS@#Most alleles were detected at locus DYS385 while fewest alleles were detected at locus DYS437 among the three nationalities. GD values were ranged from 0.2619 (DYS438) to 0.9417 (DYS385) for Miao nationality, 0.3170 (DYS391) to 0.955 9 (DYS385) for Yao nationality and 0.305 3 (DYS391) to 0.943 3 (DYS385) for Dong nationality, respectively. There were no statistically significant differences detected (P>0.05) at loci of DYS391 and DYS438 among the three nationalities.@*CONCLUSION@#The 16 Y-STR loci can be applied to practices and basic research of forensic genetics in the three main nationalities of Guangxi population.

Distinct beta-adrenergic receptor subtype signaling in the heart and their pathophysiological relevance / 生理学报

In the heart, stimulation of beta-adrenergic receptors (betaAR) serves as the most powerful means to increase cardiac contractility and relaxation in response to stress or a "fight-or-flight" situation. However, sustained beta-adrenergic stimulation promotes pathological cardiac remodeling such as myocyte hypertrophy, apoptosis and necrosis, thus contributing to the pathogenesis of chronic heart failure. Over the past decade, compelling evidence has demonstrated that coexisting cardiac betaAR subtypes, mainly beta(1)AR and beta (2)AR, activate markedly different signaling cascades. As a result, acute beta(1)AR stimulation activates the G(s) -adenylyl cyclase-cAMP-PKA signaling that can broadcast throughout the cell, whereas beta(2)AR-evoked cAMP signaling is spatially and functionally compartmentalized, due to concurrent G(i) activation. Chronic stimulation of beta(1)AR and beta(2)AR elicits opposing effects on the fate of cardiomyocytes: beta(1)AR induces hypertrophy and apoptosis; but beta(2)AR promotes cell survival. The cardiac protective effect of beta(2)AR is mediated by a signaling pathway sequentially involving G(i), G(betagamma), PI3K and Akt. Unexpectedly, beta(1)AR-induced myocyte hypertrophy and apoptosis are independent of the classic cAMP/PKA pathway, but require activation of Ca(2+)/calmodulin-dependent kinase II (CaMK II). The outcomes of cardiac-specific transgenic overexpression of either beta AR subtype in mice have reinforced the fundamentally different functional roles of these betaAR subtypes in governing cardiac remodeling and performance. These new insights regarding betaAR subtype stimulation not only provide clues as to cellular and molecular mechanisms underlying the beneficial effects of beta AR blockers in patients with chronic heart failure, but also delineate rationale for combining selective beta(1)AR blockade with moderate beta(2)AR activation as a potential novel therapy for the treatment of chronic heart failure.