Mechanisms of right ventricular (RV) dysfunction in heart failure (HF) are poorly understood. RV response to volume overload (VO), a common contributing factor to HF, is rarely studied. The goal was to identify interventricular differences in response to chronic VO. Rats underwent aorto-caval fistula (ACF)/sham operation to induce VO. After 24 weeks, RV and left ventricular (LV) functions, gene expression and proteomics were studied. ACF led to biventricular dilatation, systolic dysfunction and hypertrophy affecting relatively more RV. Increased RV afterload contributed to larger RV stroke work increment compared to LV. Both ACF ventricles displayed upregulation of genes of myocardial stress and metabolism. Most proteins reacted to VO in a similar direction in both ventricles, yet the expression changes were more pronounced in RV (pslope: < 0.001). The most upregulated were extracellular matrix (POSTN, NRAP, TGM2, CKAP4), cell adhesion (NCAM, NRAP, XIRP2) and cytoskeletal proteins (FHL1, CSRP3) and enzymes of carbohydrate (PKM) or norepinephrine (MAOA) metabolism. Downregulated were MYH6 and FAO enzymes. Therefore, when exposed to identical VO, both ventricles display similar upregulation of stress and metabolic markers. Relatively larger response of ACF RV compared to the LV may be caused by concomitant pulmonary hypertension. No evidence supports RV chamber-specific regulation of protein expression in response to VO.

• MeSH
• Extracellular Matrix Proteins genetics   metabolism   MeSH
• Rats MeSH
• Cell Adhesion Molecules genetics   metabolism   MeSH
• Myocardium metabolism   MeSH
• Rats, Sprague-Dawley MeSH
• Protein Glutamine gamma Glutamyltransferase 2 MeSH
• Proteome genetics   metabolism   MeSH
• Pyruvate Kinase genetics   metabolism   MeSH
• Ventricular Remodeling * MeSH
• Heart Ventricles metabolism   pathology   physiopathology   MeSH
• Heart Failure metabolism   pathology   physiopathology   MeSH
• Stroke Volume MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Extracellular Matrix Proteins MeSH
• Cell Adhesion Molecules MeSH
• Pkm protein, rat MeSH Browser
• Protein Glutamine gamma Glutamyltransferase 2 MeSH
• Proteome MeSH
• Pyruvate Kinase MeSH
• Tgm2 protein, rat MeSH Browser

Background: The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. We aimed to describe the prevalence, phenotypic expression, and mitochondrial function of individuals with putative disease-causing desmin (DES) variants identified in patients with an unexplained etiology of cardiomyopathy. Methods: A total of 327 Czech patients underwent whole exome sequencing and detailed phenotyping in probands harboring DES variants. Results: Rare, conserved, and possibly pathogenic DES variants were identified in six (1.8%) probands. Two DES variants previously classified as variants of uncertain significance (p.(K43E), p.(S57L)), one novel DES variant (p.(A210D)), and two known pathogenic DES variants (p.(R406W), p.(R454W)) were associated with characteristic desmin-immunoreactive aggregates in myocardial and/or skeletal biopsy samples. The individual with the novel DES variant p.(Q364H) had a decreased myocardial expression of desmin with absent desmin aggregates in myocardial/skeletal muscle biopsy and presented with familial left ventricular non-compaction cardiomyopathy (LVNC), a relatively novel phenotype associated with desminopathy. An assessment of the mitochondrial function in four probands heterozygous for a disease-causing DES variant confirmed a decreased metabolic capacity of mitochondrial respiratory chain complexes in myocardial/skeletal muscle specimens, which was in case of myocardial succinate respiration more profound than in other cardiomyopathies. Conclusions: The presence of desminopathy should also be considered in individuals with LVNC, and in the differential diagnosis of mitochondrial diseases.

• Keywords
• desmin, dilated cardiomyopathy, mitochondrial dysfunction, myopathy, non-ischemic cardiomyopathy, whole exome sequencing,
• Publication type
• Journal Article MeSH

Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. Mutations in PNPLA6 also cause human spastic paraplegia characterized by motor neuron degeneration. Here we identify PNPLA6 mutations in childhood blindness in seven families with retinal degeneration, including Leber congenital amaurosis and Oliver McFarlane syndrome. PNPLA6 localizes mostly at the inner segment plasma membrane in photoreceptors and mutations in Drosophila PNPLA6 lead to photoreceptor cell death. We also report that lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness.

• MeSH
• Retinal Degeneration genetics   MeSH
• Child MeSH
• Drosophila MeSH
• Phenotype MeSH
• Microscopy, Fluorescence MeSH
• Phospholipases genetics   physiology   MeSH
• Phospholipids chemistry   MeSH
• Spectrometry, Mass, Electrospray Ionization MeSH
• Humans MeSH
• Molecular Sequence Data MeSH
• Mutation * MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Child, Preschool MeSH
• Retina pathology   MeSH
• Pedigree MeSH
• Amino Acid Sequence MeSH
• Sequence Analysis, DNA MeSH
• Sequence Homology, Amino Acid MeSH
• Blindness genetics   MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Child, Preschool MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Phospholipases MeSH
• Phospholipids MeSH
• PNPLA6 protein, human MeSH Browser