BEX1 is a critical determinant of viral myocarditis.

Viral infection of the heart is a common but underappreciated cause of heart failure. Viruses can cause direct cardiac damage by lysing infected cardiomyocytes. Inflammatory immune responses that limit viral replication can also indirectly cause damage during infection, making regulatory factors that fine-tune these responses particularly important. Identifying and understanding these factors that regulate cardiac immune responses during infection will be essential for developing targeted treatments for virus-associated heart failure. Our laboratory has discovered Brain Expressed X-linked protein 1 (BEX1) as a novel stress-regulated pro-inflammatory factor in the heart. Here we report that BEX1 plays a cardioprotective role in the heart during viral infection. Specifically, we adopted genetic gain- and loss-of-function strategies to modulate BEX1 expression in the heart in the context of coxsackievirus B3 (CVB3)-induced cardiomyopathy and found that BEX1 limits viral replication in cardiomyocytes. Interestingly, despite the greater viral load observed in mice lacking BEX1, inflammatory immune cell recruitment in the mouse heart was profoundly impaired in the absence of BEX1. Overall, the absence of BEX1 accelerated CVB3-driven heart failure and pathologic heart remodeling. This result suggests that limiting inflammatory cell recruitment has detrimental consequences for the heart during viral infections. Conversely, transgenic mice overexpressing BEX1 in cardiomyocytes revealed the efficacy of BEX1 for counteracting viral replication in the heart in vivo. We also found that BEX1 retains its antiviral role in isolated cells. Indeed, BEX1 was necessary and sufficient to counteract viral replication in both isolated primary cardiomyocytes and mouse embryonic fibroblasts suggesting a broader applicability of BEX1 as antiviral agent that extended to viruses other than CVB3, including Influenza A and Sendai virus. Mechanistically, BEX1 regulated interferon beta (IFN-ß) expression in infected cells. Overall, our study suggests a multifaceted role of BEX1 in the cardiac antiviral immune response.

CCN2 participates in overload-induced skeletal muscle hypertrophy.

The regulation of skeletal muscle growth following pro-hypertrophic stimuli requires a coordinated response by different cell types that leads to extracellular matrix (ECM) remodeling and increases in muscle cross-sectional area. Indeed, matricellular proteins serve a key role as communication vehicles that facilitate the propagation of signaling stimuli required for muscle adaptation to environmental challenges. We found that the matricellular protein cellular communication network factor 2 (CCN2), also known as connective tissue growth factor (CTGF), is induced during a time course of overload-driven skeletal muscle hypertrophy in mice. To elucidate the role of CCN2 in mediating the hypertrophic response, we utilized genetically engineered mouse models for myofiber-specific CCN2 gain- and loss-of-function and then examined their response to mechanical stimuli through muscle overload. Interestingly, myofiber-specific deletion of CCN2 blunted muscle's hypertrophic response to overload without interfering with ECM deposition. On the other hand, when in excess through transgenic CCN2 overexpression, CCN2 was efficient in promoting overload-induced aberrant ECM accumulation without affecting myofiber growth. Altogether, our genetic approaches highlighted independent ECM and myofiber stress adaptation responses, and positioned CCN2 as a central mediator of both. Mechanistically, CCN2 acts by regulating focal adhesion kinase (FAK) mediated transduction of overload-induced extracellular signals, including interleukin 6 (IL6), and their regulatory impact on global protein synthesis in skeletal muscle. Overall, our study highlights the contribution of muscle-derived extracellular matrix factor CCN2 for proper hypertrophic muscle growth.

Viruses in the Heart: Direct and Indirect Routes to Myocarditis and Heart Failure.

Viruses are an underappreciated cause of heart failure. Indeed, several types of viral infections carry cardiovascular risks. Understanding shared and unique mechanisms by which each virus compromises heart function is critical to inform on therapeutic interventions. This review describes how the key viruses known to lead to cardiac dysfunction operate. Both direct host-damaging mechanisms and indirect actions on the immune systems are discussed. As viral myocarditis is a key pathologic driver of heart failure in infected individuals, this review also highlights the role of cytokine storms and inflammation in virus-induced cardiomyopathy.

Cardiac-derived TGF-ß1 confers resistance to diet-induced obesity through the regulation of adipocyte size and function.

Regulation of organismal homeostasis in response to nutrient availability is a vital physiological process that involves inter-organ communication. Understanding the mechanisms controlling systemic cross-talk for the maintenance of metabolic health is critical to counteract diet-induced obesity. Here, we show that cardiac-derived transforming growth factor beta 1 (TGF-ß1) protects against weight gain and glucose intolerance in mice subjected to high-fat diet. Secretion of TGF-ß1 by cardiomyocytes correlates with the bioavailability of this factor in circulation. TGF-ß1 prevents adipose tissue inflammation independent of body mass and glucose metabolism phenotypes, indicating protection from adipocyte dysfunction-driven immune cell recruitment. TGF-ß1 alters the gene expression programs in white adipocytes, favoring their fatty acid oxidation and consequently increasing their mitochondrial oxygen consumption rates. Ultimately, subcutaneous and visceral white adipose tissue from cadiac-specific TGF-ß1 transgenic mice fail to undergo cellular hypertrophy, leading to reduced overall adiposity during high-fat feeding. Thus, TGF-ß1 is a critical mediator of heart-fat communication for the regulation of systemic metabolism.

Epitranscriptomics in the Heart: a Focus on m6A.

PURPOSE OF REVIEW: Post-transcriptional modifications are key regulators of gene expression that allow the cell to respond to environmental stimuli. The most abundant internal mRNA modification is N6-methyladenosine (m6A), which has been shown to be involved in the regulation of RNA splicing, localization, translation, and decay. It has also been implicated in a wide range of diseases, and here, we review recent evidence of m6A's involvement in cardiac pathologies and processes. RECENT FINDINGS: Studies have primarily relied on gain and loss of function models for the enzymes responsible for adding and removing the m6A modification. Results have revealed a multifaceted role for m6A in the heart's response to myocardial infarction, pressure overload, and ischemia/reperfusion injuries. Genome-wide analyses of mRNAs that are differentially methylated during cardiac stress have highlighted the importance of m6A in regulating the translation of specific categories of transcripts implicated in pathways such as calcium handling, cell growth, autophagy, and adrenergic signaling in cardiomyocytes. Regulation of gene expression by m6A is critical for cardiomyocyte homeostasis and stress responses, suggesting a key role for this modification in cardiac pathophysiology.

Cardiovascular inflammation: RNA takes the lead.

Inflammation has recently gained tremendous attention as a key contributor in several chronic diseases. While physiological inflammation is essential to counter a wide variety of damaging stimuli and to improve wound healing, dysregulated inflammation such as in the myocardium and vasculature can promote cardiovascular diseases. Given the high severity, prevalence, and economic burden of these diseases, understanding the factors involved in the regulation of physiological inflammation is essential. Like other complex biological phenomena, RNA-based processes are emerging as major regulators of inflammatory responses. Among such processes are cis-regulatory elements in the mRNA of inflammatory genes, noncoding RNAs directing the production or localization of inflammatory cytokines/chemokines, or pathogenic RNA driving inflammatory responses. In this review, we describe several specific RNA-based molecular mechanisms by which physiological inflammation pertaining to cardiovascular diseases is regulated. These include the role of AU-rich element-containing mRNAs, long non-coding RNAs, microRNAs, and viral RNAs.