Increased Cardiac Myocyte PDE5 Levels in Human and Murine Pressure Overload Hypertrophy Contribute to Adverse LV Remodeling

Background

The intracellular second messenger cGMP protects the heart under pathological conditions. We examined expression of phosphodiesterase 5 (PDE5), an enzyme that hydrolyzes cGMP, in human and mouse hearts subjected to sustained left ventricular (LV) pressure overload. We also determined the role of cardiac myocyte-specific PDE5 expression in adverse LV remodeling in mice after transverse aortic constriction (TAC).

Methodology/Principal Findings

In patients with severe aortic stenosis (AS) undergoing valve replacement, we detected greater myocardial PDE5 expression than in control hearts. We observed robust expression in scattered cardiac myocytes of those AS patients with higher LV filling pressures and BNP serum levels. Following TAC, we detected similar, focal PDE5 expression in cardiac myocytes of C57BL/6NTac mice exhibiting the most pronounced LV remodeling. To examine the effect of cell-specific PDE5 expression, we subjected transgenic mice with cardiac myocyte-specific PDE5 overexpression (PDE5-TG) to TAC. LV hypertrophy and fibrosis were similar as in WT, but PDE5-TG had increased cardiac dimensions, and decreased dP/dt_max and dP/dt_min with prolonged tau (P<0.05 for all). Greater cardiac dysfunction in PDE5-TG was associated with reduced myocardial cGMP and SERCA2 levels, and higher passive force in cardiac myocytes in vitro.

Conclusions/Significance

Myocardial PDE5 expression is increased in the hearts of humans and mice with chronic pressure overload. Increased cardiac myocyte-specific PDE5 expression is a molecular hallmark in hypertrophic hearts with contractile failure, and represents an important therapeutic target.     

A yeast-based model of alpha-synucleinopathy identifies compounds with therapeutic potential

We have developed a yeast-based model recapitulating neurotoxicity of alpha-synuclein fibrilization. This model recognized metal ions, known risk factors of alpha-synucleinopathy, as stimulators of alpha-synuclein aggregation and cytotoxicity. Elimination of Yca1 caspase activity augmented both cytotoxicity and inclusion body formation, suggesting the involvement of apoptotic pathway components in toxic alpha-synuclein amyloidogenesis. Deletion of hydrophobic amino acids at positions 66-74 in alpha-synuclein reduced its cytotoxicity but, remarkably, did not lower the levels of insoluble alpha-synuclein, indicating that noxious alpha-synuclein species are different from insoluble aggregates. A compound screen aimed at finding molecules with therapeutic potential identified flavonoids with strong activity to restrain alpha-synuclein toxicity. Subsequent structure-activity analysis elucidated that these acted by virtue of anti-oxidant and metal-chelating activities. In conclusion, this yeast-cell model as presented allows not only fundamental studies related to mechanisms of alpha-synuclein-instigated cellular degeneration, but is also a valid high-throughput identification tool for novel neuroprotective agents.     

The relative value of strain and strain rate for defining intrinsic myocardial function

It is well accepted that strain and strain rate deformation parameters are not only a measure of intrinsic myocardial contractility but are also influenced by changes in cardiac load and structure. To date, no information is available on the relative importance of these confounders. This study was designed to investigate how strain and strain rate, measured by Doppler echocardiography, relate to the individual factors that determine cardiac performance. Echocardiographic and conductance measurements were simultaneously performed in mice in which individual determinants of cardiac performance were mechanically and/or pharmacologically modulated. A multivariable analysis was performed with radial and circumferential strains and peak systolic radial and circumferential strain rates as dependent parameters and preload recruitable stroke work (PRSW), arterial elastance (E(a)), end-diastolic pressure, and left ventricular myocardial volume (LVMV) as independent factors representing myocardial contractility, afterload, preload, and myocardial volume, respectively. Radial strain was most influenced by E(a) (β = -0.58, R(2) = 0.34), whereas circumferential strain was strongly associated with E(a) and moderately with LVMV (β = 0.79 and -0.52, respectively, R(2) = 0.54). Radial strain rate was related to both PRSW and LVMV (β = 0.79 and -0.62, respectively, R(2) = 0.50), whereas circumferential strain rate showed a prominent correlation only with PRSW (β = -0.61, R(2) = 0.51). In conclusion, strain (both radial and circumferential) is not a good surrogate measure of intrinsic myocardial contractility unless the strong confounding influence of afterload is considered. Strain rate is a more robust measure of contractility that is less influenced by changes in cardiac load and structure. Thus, peak systolic strain rate is the more relevant parameter to assess myocardial contractile function noninvasively.     

Indomethacin stimulation of macrophage cytostasis against MOPC-315 tumor cells is inhibited by both prostaglandin E2 and nordihydroguaiaretic acid,a lipoxygenase inhibitor

Summary Indomethacin enhanced macrophage cytostasis against MOPC-315 tumor cells in vitro. The effect of indomethacin was inhibited by prostaglandin E₂ and by the lipoxygenase inhibitor nordihydroguaiaretic acid. Prostaglandin E₂ and nordihydroguaiaretic acid also inhibited indomethacin stimulation of macrophage thymidine incorporation. Indomethacin inhibited macrophage prostaglandin E₂ formation and stimulated leukotriene B₄ synthesis. Nordihydroguaiaretic acid inhibited leukotriene B₄ production. Our data indicate that eicosanoids play a role in regulating macrophage cytostasis.     

Climate and Soil Type Together Explain the Distribution of Microendemic Species in a Biodiversity Hotspot

The grasshopper genus Caledonula, endemic to New Caledonia, was studied to understand the evolution of species distributions in relation to climate and soil types. Based on a comprehensive sampling of 80 locations throughout the island, the genus was represented by five species, four of which are new to science, of which three are described here. All the species have limited distributions in New Caledonia. Bioclimatic niche modelling shows that all the species were found in association with a wet climate and reduced seasonality, explaining their restriction to the southern half of the island. The results suggest that the genus was ancestrally constrained by seasonality. A molecular phylogeny was reconstructed using two mitochondrial and two nuclear markers. The partially resolved tree showed monophyly of the species found on metalliferous soils, and molecular dating indicated a rather recent origin for the genus. Adaptation to metalliferous soils is suggested by both morphological changes and radiation on these soils. The genus Caledonula is therefore a good model to understand the origin of microendemism in the context of recent and mixed influences of climate and soil type.     

The conservation-refugium value of small and disturbed Brazilian Atlantic forest fragments for the endemic ovoviviparous cockroach Monastria biguttata (Insecta: Dictyoptera, Blaberidae, Blaberinae)

The Brazilian Atlantic forest is a biodiversity hotspot and harbors many endemic species showing peculiar and unique traits. However, it has been reduced to less than 8% of its original surface and is distributed in scattered fragments, the great majority of which are smaller than 20 hectares and very disturbed, making it worth asking about their value for conservation. In this paper we assess the refugium value of small fragments to the conservation of one of the endemics of the Atlantic forest, the ovoviviparous cockroach Monastria biguttata. Our results showed that this species was ubiquitous in large and small forest fragments, but never present in plantations or pastures. The population age structure and sex ratio were balanced in every fragment, and total population size in the smallest fragments was at least several hundreds of individuals. Colony size, sex ratio, age structure, and density per piece of dead tree trunk indicated that populations from small fragments were not unbalanced or at risk of extinction. According to the analysis of resource availability, small fragments can provide suitable habitat for this species. In this situation, even very small forest fragments have a high refugium value for some endemic insect species. Considering their number in the landscape, these fragments should be considered with more attention in strategies of biodiversity conservation.     

Evolution on a shaky piece of Gondwana: is local endemism recent in New Caledonia?

New Caledonia is well known as a hot spot of biodiversity whose origin as a land mass can be traced back to the Gondwanan supercontinent. The local flora and fauna, in addition to being remarkably rich and endemic, comprise many supposedly relictual groups. Does the New Caledonian biota date back to Gondwanan times, building up its richness and endemism over 100 Myr or does it result from recent diversifications after Tertiary geological catastrophic events? Here we use a molecular phylogenetic approach to answer this question with the study of the Neocaledonian cockroach genus Angustonicus belonging to the subfamily Tryonicinae from Australia and New Caledonia. Both geological and molecular dating show that the diversification of this group is less than two million years old, whatever the date of its origin itself. This dating is not consistent with hypotheses of Gondwanan richness and endemism in New Caledonian biota. In other terms, local richness and endemism at the specific level are not necessarily related to an old Gondwanan origin of the Neocaledonian groups. © The Willi Hennig Society 2005.     

High evolutionary and functional distinctiveness of endemic monocots in world islands

Functionally and evolutionarily distinct species have traits or an evolutionary history that are shared by few others in a given set, which make them priority species for biodiversity conservation. On islands, life in isolation has led to the evolution of many distinct forms and functions as well as to a high level of endemism. The aim of this study is to assess the evolutionary and functional distinctiveness of insular monocotyledons and their distribution across 126 islands worldwide. We show that evolutionary and functional distinctiveness are decoupled but that both are higher on islands than on continental areas. Anagenesis on islands followed by extinctions and/or diversification on the mainland may have led to highly evolutionarily distinct species while functionally distinct species may have arisen from ecological niche shift or niche expansion. Insular endemic species with high evolutionary distinctiveness but not with high functional distinctiveness are significantly range-restricted compared to less distinct species, possibly indicating differences in dispersal potential. By showing that distinctiveness is high on islands and that the most distinct species are range-restricted, our study has important conservation implications. Indeed, islands are among the most threatened systems of the world, and extinctions of the most distinct species could lead to significant loss of phylogenetic and functional diversity.

     

A Comparison of Behavioral Interactions in Solitary and Presocial Zetoborinae Cockroaches (Blattaria,Blaberidae)

The social behavior of five species of Zetoborinae cockroaches is compared with respect to inter-individual interactions of nymphs in the laboratory. These species belong to the same Neotropical subfamily and were characterized as gregarious (Lanxoblatta emarginata, Parasphaeria boleiriana, Phortioeca nimbata, Schultesia lampyridiformis) and solitary (Thanatophyllum akinetum) by previous field studies. Our results show that gregarious species accept closer contacts than does the solitary one. The solitary species did not display especially short, infrequent or less diverse behavioral sequences when forced to remain aggregated, but its interactions are characterized by fewer acts promoting contact and more dominance-like acts. The solitary species symmetrically interacts with conspecifics and does not show specific dispersal-promoting behaviors. This suggests that the solitary behavior observed in the field for species of Zetoborinae mainly results from a passive spacing tendency and a lack of attraction for conspecifics. One of the gregarious species, P. boleiriana, was previously described as subsocial with nymphs remaining with the female in a wood chamber after brood birth. This species does not show a peculiar behavioral repertoire but its interactions are characterized by more dominance-like behaviors than are those of the non-subsocial gregarious species. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.