Distinct lipidomic profiles in models of physiological and pathological cardiac remodeling,and potential therapeutic strategies

Cardiac myocyte membranes contain lipids which remodel dramatically in response to heart growth and remodeling. Lipid species have both structural and functional roles. Physiological and pathological cardiac remodeling have very distinct phenotypes, and the identification of molecular differences represent avenues for therapeutic interventions. Whether the abundance of specific lipid classes is different in physiological and pathological models was largely unknown. The aim of this study was to determine whether distinct lipids are regulated in settings of physiological and pathological remodeling, and if so, whether modulation of differentially regulated lipids could modulate heart size and function. Lipidomic profiling was performed on cardiac-specific transgenic mice with 1) physiological cardiac hypertrophy due to increased Insulin-like Growth Factor 1 (IGF1) receptor or Phosphoinositide 3-Kinase (PI3K) signaling, 2) small hearts due to depressed PI3K signaling (dnPI3K), and 3) failing hearts due to dilated cardiomyopathy (DCM). In hearts of dnPI3K and DCM mice, several phospholipids (plasmalogens) were decreased and sphingolipids increased compared to mice with physiological hypertrophy. To assess whether restoration of plasmalogens could restore heart size or cardiac function, dnPI3K and DCM mice were administered batyl alcohol (BA; precursor to plasmalogen biosynthesis) in the diet for 16 weeks. BA supplementation increased a major plasmalogen species (p18:0) in the heart but had no effect on heart size or function. This may be due to the concurrent reduction in other plasmalogen species (p16:0 and p18:1) with BA. Here we show that lipid species are differentially regulated in settings of physiological and pathological remodeling. Restoration of lipid species in the failing heart warrants further examination.     

Untargeted metabolomics analysis of ischemia–reperfusion-injured hearts ex vivo from sedentary and exercise-trained rats

Introduction

The effects of exercise on the heart and its resistance to disease are well-documented. Recent studies have identified that exercise-induced resistance to arrhythmia is due to the preservation of mitochondrial membrane potential.

Objectives

To identify novel metabolic changes that occur parallel to these mitochondrial alterations, we performed non-targeted metabolomics analysis on hearts from sedentary and exercise-trained rats challenged with isolated heart ischemia–reperfusion injury (I/R).

Methods

Eight-week old Sprague–Dawley rats were treadmill trained 5 days/week for 6 weeks (exercise duration and intensity progressively increased to 1 h at 30 m/min up a 10.5% incline, 75–80% VO_2max). The recovery of pre-ischemic function for sedentary rat hearts was 28.8?±?5.4% (N?=?12) compared to exercise trained hearts, which recovered 51.9%?±?5.7 (N?=?14) (p?<?0.001).

Results

Non-targeted GC–MS metabolomics analysis of (1) sedentary rat hearts; (2) exercise-trained rat hearts; (3) sedentary rat hearts challenged with global ischemia–reperfusion (I/R) injury; and (4) exercise-trained rat hearts challenged with global I/R (10/group) revealed 15 statistically significant metabolites between groups by ANOVA using Metaboanalyst (p?<?0.001). Enrichment analysis of these metabolites for pathway-associated metabolic sets indicated a?>?10-fold enrichment for ammonia recycling and protein biosynthesis. Subsequent comparison of the sedentary hearts post-I/R and exercise-trained hearts post-I/R further identified significant differences in three metabolites (oleic acid, pantothenic acid, and campesterol) related to pantothenate and CoA biosynthesis (p?≤?1.24E?05, FDR?≤?5.07E?4).

Conclusions

These studies shed light on novel mechanisms in which exercise-induced cardioprotection occurs in I/R that complement both the mitochondrial stabilization and antioxidant mechanisms recently described. These findings also link protein synthesis and protein degradation (protein quality control mechanisms) with exercise-linked cardioprotection and mitochondrial susceptibility for the first time in cardiac I/R.

     

Detection of Salmonella by a Single-Culture Technique

Dulcitol-selenite enrichment medium in a motility flask was used for the detection of Salmonella in food. A drop in pH of the dulcitol-selenite enrichment motility broth indicated the presence of Salmonella; this phenomenon was confirmed by fluorescent-antibody staining. A complete correlation was found between fluorescent-antibody staining and recovery on Brilliant Green agar. Testing of 332 samples of 8 different kinds of foods and feeds indicated no significant difference in sensitivity between the new technique and a conventional Salmonella detection technique. The new technique permitted detection of even small numbers of Salmonella in 1 to 2 days.     

Microbial Hydroxylation of Indole Alkaloids

The hydroxylation of the indole-type alkaloids, yohimbine, α-yohimbine, β-yohimbine, and corynanthine, was achieved with several genera of higher fungi and species of Streptomyces. Microorganisms were found which monohydroxylated these compounds in three different positions. The site of hydroxylation was strain-specific for two strains of Cunninghamella echinulata and C. bainieri.     

Phosphorylated EGFR Dimers Are Not Sufficient to Activate Ras

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