Thenappan, T. | bioRxiv Science

bioRxiv2024

Lactobacillus Restructures the Micro/Mycobiome to Combat Glycoprotein-130 Associated Microtubule Remodeling and Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

Emerging data demonstrate systemic and local inflammation regulate right ventricular (RV) adaption in preclinical and human pulmonary arterial hypertension (PAH). Pathological RV inflammation is targetable as antagonism of glycoprotein-130 (GP130) signaling counteracts pathological microtubule remodeling and improves RV function in rodents. Microtubules control several aspects of cardiomyocyte biology including cellular and nuclear size/structure, t-tubule homeostasis, and the proper localization of connexin-43. The intestinal microbiome regulates systemic inflammation, but the impact of the gut microbiome on the GP130-microtubule axis in RV failure is unknown. Here, we examined how the anti-inflammatory bacteria, Lactobacillus, modulated cellular and physiological RV phenotypes in preclinical and clinical PAH. Lactobacillus supplementation restructured the gut micro/mycobiome, suppressed systemic inflammation, combatted pathological GP130-mediated RV cardiomyocyte microtubule remodeling, and augmented RV function in rodent PAH. Moreover, Lactobacillus was associated with superior RV adaption in human PAH. These data further support the hypothesis that inflammation negatively impacts RV adaption in PAH, and identify the gut microbiome as a potentially targetable regulator of RV function in PAH.

physiology↗

bioRxiv2023

Ketone bodies in Right Ventricular Failure: A Unique Therapeutic Opportunity

Introductory ParagraphKetone bodies are pleotropic metabolites that play important roles in multiple biological processes ranging from bioenergetics to inflammation regulation via suppression of the NLRP3 inflammasome, and epigenetic modifications. Ketone bodies are elevated in left ventricular failure (LVF) and multiple approaches that increase ketone concentrations exert advantageous cardiac effects in rodents and humans. However, the relationships between ketone bodies and right ventricular failure (RVF) are relatively unexplored. Moreover, the cardioprotective properties of ketones in preclinical RVF are unknown. Here, we show a compensatory ketosis is absent in pulmonary arterial hypertension (PAH) patients with RVF. In the monocrotaline (MCT) rat model of PAH-mediated RVF, a dietary-induced ketosis improves RV function, suppresses NLRP3 inflammasome activation, and combats RV fibrosis. The summation of these data suggest ketogenic therapies may be particularly efficacious in RVF, and therefore future studies evaluating ketogenic interventions in human RVF are warranted.

biochemistry↗

bioRxiv2021

With No Lysine Kinase 1 Promotes Right Ventricular Dysfunction Via Glucotoxicity

ObjectivesInvestigate how WNK1 inhibition modulates glucotoxicity, mitochondrial/peroxisomal protein regulation and metabolism, and right ventricular (RV) function in pulmonary arterial hypertension (PAH). Determine how hypochloremia impacts RV function in PAH patients. BackgroundIn PAH-induced RV failure, GLUT1/GLUT4 expression is elevated, which increases glucose uptake and glycolytic flux to compensate for mitochondrial dysfunction. However, the resultant consequences of the glucose-mediated post-translational modifications (PTM), protein O-GlcNAcylation/glycation in RV failure are understudied. WNK1, a chloride-sensitive kinase, increases GLUT1/GLUT4 expression in skeletal muscle, but its regulation in RV dysfunction is unexplored. MethodsRats were treated with WNK463 (small molecule WNK inhibitor) or vehicle starting two weeks after monocrotaline injection. Immunoblots quantified protein abundance/PTMs. Mitochondrial/peroxisomal proteomics and global metabolomics evaluated glucose metabolism and mitochondrial/peroxisomal function. Pulmonary vascular and cardiac histology, echocardiography, and pressure-volume loop analysis quantified RV function and PAH severity. Finally, the relationship between hypochloremia, a WNK1-activating state, and RV function was evaluated in 217 PAH patients. ResultsWNK463 decreased WNK1/GLUT1/GLUT4 expression, normalized glucose metabolite levels, which dampened excess protein O-GlcNAcylation/glycation. Integration of RV mitochondrial/peroxisomal proteomics and metabolomics identified fatty acid oxidation (FAO) as the most dysregulated metabolic pathway. WNK463 enhanced FAO as demonstrated by increased expression of mitochondrial FAO proteins and normalization of RV acylcarnitines. WNK463 reduced glutaminolysis induction and lipotoxicity, two secondary consequences of diminished FAO. WNK463 augmented RV systolic and diastolic function independent of pulmonary vascular disease severity. In PAH patients, hypochloremia resulted in more severe RV dysfunction. ConclusionsWNK463 combated RV glucotoxicity and impaired FAO, which directly improved RV function. HighlightsO_LISmall molecule inhibition of WNK1 (WNK463) signaling mitigates upregulation of the membrane glucose channels GLUT1 and GLUT4, restores levels of several glucose metabolites, and normalizes protein O-GlcNAcylation and glycation in the RV. C_LIO_LIQuantitative proteomics of RV mitochondrial enrichments shows WNK463 treatment prevents downregulation of mitochondrial enzymes in the tricarboxylic acid cycle, fatty acid oxidation pathway, and the electron transport chain complexes. C_LIO_LIIntegration of proteomics and metabolomics analysis reveals WNK463 reduces glutaminolysis induction and lipotoxicity due to impaired fatty acid oxidation C_LIO_LIWNK463 augments RV systolic and diastolic function independent of PAH severity. C_LIO_LIHypochloremia, a condition of predicted WNK1 activation, in PAH patients results in more severe RV dysfunction. C_LI

physiology↗