Pseudouridine and N-formylmethionine associate with left ventricular mass index: Metabolome-wide association analysis of cardiac remodeling.

BACKGROUND: Heart failure (HF) is the fastest growing form of cardiovascular disease both nationally and globally, underlining a need to phenotype subclinical HF intermediaries to improve primary prevention. OBJECTIVES: We aimed to identify novel metabolite associations with left ventricular (LV) remodeling, one upstream HF intermediary, among a community-based cohort of individuals. METHODS: We examined 1052 Bogalusa Heart Study participants (34.98% African American, 57.41% female, aged 33.6-57.5 years). Measures of LV mass and relative wall thickness (RWT) were obtained using two-dimensional-guided echocardiographic measurements via validated eqs. LV mass was indexed to height2.7 to calculate left ventricular mass index (LVMI). Untargeted metabolomic analysis of fasting serum samples was conducted. In combined and ethnicity-stratified analyses, multivariable linear and multinomial logistic regression models tested the associations of metabolites with the continuous LVMI and RWT and categorical LV geometry phenotypes, respectively, after adjusting for demographic and traditional cardiovascular disease risk factors. RESULTS: Pseudouridine (B = 1.38; p = 3.20 × 10-5) and N-formylmethionine (B = 1.65; 3.30 × 10-6) were significantly associated with LVMI in the overall sample as well significant in Caucasians, with consistent effect direction and nominal significance (p < .05) in African Americans. Upon exclusion of individuals with self-report myocardial infarction or congestive HF, we similarly observed a 1.33 g/m2.7 and 1.52 g/m2.7 higher LVMI for each standard deviation increase in pseudouridine and N-formylmethionine, respectively. No significant associations were observed for metabolites with RWT or categorical LV remodeling outcomes. CONCLUSIONS: The current analysis identified novel associations of pseudouridine and N-formylmethionine with LVMI, suggesting that mitochondrial-derived metabolites may serve as early biomarkers for LV remodeling and subclinical HF.

Reversible pinocytosis in polymorphonuclear leukocytes.

Since pinocytosis has only been recently recognized in polymorphonuclear leukocytes (PMNs), little is known about the fate of pinosomes. Here we report that pinosomes can fuse with the cytoplasmic granules of PMNs. We also find that at least for a short period of time after formation, pinosomes can fuse with the plasma membrane and release their contents to the outside. We present a morphological description and biochemical data on the kinetic parameters of a steady state pool of reversible pinosomes in PMNs. In addition, we have developed conditions under which pinosomes continue to form and fuse with the plasma membrane but fail to fuse with the cytoplasmic granules, i.e., only "reversible" pinocytosis occurs. This inhibition of fusion with the granules is not due to an inability of the pinosomes to move from the surface since under these conditions pinosomes labeled with an electron-dense marker can be seen in the cell interior.

The effect of hemin, adenosine 3',5'-monophosphate and phosphorylated sugars on Met-tRNAfMet deacylase activity in rabbit reticulocyte lysates.

The effect of hemin, phosphorylated sugars, adenosine 3',5'-monophosphate (cyclic AMP) and a number of purines on a specific initiator tRNA deacylase activity in rabbit reticulocytes has been investigated. In the concentration range established to be optimal for maximal stimulation of translation (5.5-30.0 microM), hemin produces a 20-82% inhibition of Met-tRNAfMet deacylation. In contrast, all phosphorylated sugars tested, with the exception of fructose 1,6-diphosphate, are without effect. High concentrations of cyclic AMP (2-4 mM) also significantly inhibit the deacylase activity. The role of hemin and Met-tRNAfMet deacylase in the control of peptide initiation are discussed.

Adaptation of human neutrophil responsiveness to the chemoattractant N-formylmethionylleucylphenylalanine. Heterogeneity and/or negative cooperative interaction of receptors.

The dose-response characteristics of the neutrophil 3-3'-dipentyloxacarbocyanine (di-O-C5(3)) fluorescence response to repetitive stimulation with the chemoattractant N-formylmethionylleucylphenylalanine (fMet-Leu-Phe) were studied. Neutrophils exposed to the chemoattractant fMet-Leu-Phe at less than 5 X 10(-8) M subsequently responded only to higher concentrations of fMet-Leu-Phe. This stimulus-induced modification of neutrophil responsiveness involved a reversible fMet-Leu-Phe-induced shift in response Km (the concentration of fMet-Leu-Phe producing a half-maximal response) to higher values which occurred 1 to 2 min after exposure to fMet-Leu-Phe and represented a form of adaptation. A Hill coefficient of 0.68 +/- 0.07 was determined from analysis of the data indicating that the di-O-C5(3) fluorescence response behavior is compatible with functional negatively cooperative interaction and/or heterogeneity of fMet-Leu-Phe receptors. In related studies, analysis of the binding of fMet-Leu-[3H]Phe to intact cells and cell-free plasma membrane preparations resulted in Hill coefficients of 0.64 +/- 0.06 and 0.69 +/- 0.07, respectively, indicating that fMet-Leu-Phe binding exhibits properties similar to the fMet-Leu-Phe-elicited di-O-C5(3) fluorescence response. Modulation of receptor affinity, through either negative cooperativity or changing populations of heterogeneous receptors, may be an important mechanism by which neutrophils adapt and respond to a gradient of chemoattractant during the process of chemotaxis.