Cyclic Nucleotide Phosphodiesterases and Compartmentation in Normal and Diseased Heart

International audienceCyclic nucleotide phosphodiesterases (PDEs) degrade the second messengers cAMP and cGMP, thereby regulating multiple aspects of cardiac function. This highly diverse class of enzymes encoded by 21 genes encompasses 11 families which are not only responsible for the termination of cyclic nucleotide signalling, but are also involved in the generation of dynamic microdomains of cAMP and cGMP controlling specific cell functions in response to various neurohormonal stimuli. In myocardium, the PDE3 and PDE4 families are predominant to degrade cAMP and thereby regulate cardiac excitation-contraction coupling. PDE3 inhibitors are positive inotropes and vasodilators in human, but their use is limited to acute heart failure and intermittent claudication. PDE5 is particularly important to degrade cGMP in vascular smooth muscle, and PDE5 inhibitors are used to treat erectile dysfunction and pulmonary hypertension. However, these drugs do not seem efficient in heart failure with preserved ejection fraction. There is experimental evidence that these PDEs as well as other PDE families including PDE1, PDE2 and PDE9 may play important roles in cardiac diseases such as hypertrophy and heart failure. After a brief presentation of the cyclic nucleotide pathways in cardiac cells and the major characteristics of the PDE superfamily, this chapter will present their role in cyclic nucleotide compartmentation and the current use of PDE inhibitors in cardiac diseases together with the recent research progresses that could lead to a better exploitation of the therapeutic potential of these enzymes in the future

Differences in Circulating microRNAs between Grazing and Grain-Fed Wagyu Cattle Are Associated with Altered Expression of Intramuscular microRNA, the Potential Target PTEN, and Lipogenic Genes.

We aimed to understand the roles of miRNAs in the muscle tissue maturation and those of circulating microRNAs (c-miRNAs) in beef production of Japanese Black (JB) cattle (Wagyu), a breed with genetically background of superior intermuscular fat depot, by comparing different feeding conditions (indoor grain-feeding vs. grazing on pasture). The cattle at 18 months old were assigned to pasture feeding or conventional indoor grain feeding conditions for 5 months. Microarray analysis of c-miRNAs from the plasma extracellular vesicles led to the detection of a total of 202 bovine miRNAs in the plasma, including 15 miRNAs that differed between the feeding conditions. Validation of the microarray results by qPCR showed that the circulating miR-10b level in the grazing cattle was upregulated compared to that of the grain-fed cattle. In contrast, the levels of miR-17-5p, miR-19b, miR-29b, miR-30b-5p, miR-98, miR-142-5p, miR-301a, miR-374b, miR-425-5p, and miR-652 were lower in the grazing cattle than in the grain-fed cattle. Bioinformatic analysis indicated that the predicted target genes of those c-miRNAs were enriched in gene ontology terms associated with blood vessel morphogenesis, plasma membrane, focal adhesion, endocytosis, collagen, ECM-receptor interaction, and phosphorylation. In the grazing cattle, the elevation of miR-10b expression in the plasma was coincident with its elevation in the longissimus lumborum (LL) muscle. Expression of bovine-specific miR-2478, the most plasma-enriched miRNA, tended to be also upregulated in the muscle but not in the plasma. Furthermore, grazing caused the downregulated mRNA expression of predicted miR-10b and/or miR-2478 target genes, such as DNAJB2, PTEN, and SCD1. Thus, the feeding system used for JB cattle affected the c-miRNAs that could be indicators of grain feeding. Among these, miR-10b expression was especially associated with feeding-induced changes and with the expression of the potential target genes responsible for glucose homeostasis and intramuscular fat depot in the LL muscle of JB cattle

Proteomic analysis of secreted proteins from skeletal muscle cells during differentiation

Myokines are muscle-secreted factors to regulate cellular functions. However, it remains elusive what type of myokine is released during muscle differentiation. Here we evaluated the dynamics of myokines. More than 400 proteins were detected in conditioned medium and approximately 8% of them were categorized as myokines. The levels of myokines which promote myotube formation, vascularization or neurogenesis peaked during early differentiation, whereas myokines contributing to repellent activity against nerve cells or suppression of adipogenesis decreased after differentiation. Our findings suggest that muscle cells secrete different types of myokines at different developmental stages to communicate with various types of cells

Circulating miRNA expression in plasma extracellular vesicles of grain-fed and grazing Japanese Black cattle analyzed by qRT-PCR.

<p>** and * indicate the differences between the feeding conditions at <i>P</i> < 0.01 and < 0.05, respectively.</p

Chemical composition of grass on pasture during grazing of cattle.

<p>Chemical composition of grass on pasture during grazing of cattle.</p

Potential cellular biological events predicted from the microRNA target genes.

<p>Potential cellular biological events predicted from the microRNA target genes.</p

Top 20 c-miRNAs considered as significantly different between feeding conditions of JB cattle.

<p>Top 20 c-miRNAs considered as significantly different between feeding conditions of JB cattle.</p

Circulating miRNA (c-miRNA) profiles in plasma extracellular vesicles of Japanese Black cattle obtained in microarray analysis.

<p>Percentages of c-miRNA contents in grain-fed (red bars) and grazing cattle (green bars) are indicated. The top 20 miRNAs in plasma of grazing cattle are listed.</p

miRNA target gene expression in <i>longissimus lumborum</i> muscle of grain-fed and grazing Japanese Black cattle analyzed by qRT-PCR.

<p>* and + indicate the differences between the feeding conditions at <i>P</i> < 0.05 and < 0.10, respectively.</p