Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide.

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies.

l-Carnitine therapy improves right heart dysfunction through Cpt1-dependent fatty acid oxidation.

Pulmonary arterial hypertension (PAH) is a fatal vasculopathy that ultimately leads to elevated pulmonary pressure and death by right ventricular (RV) failure, which occurs in part due to decreased fatty acid oxidation and cytotoxic lipid accumulation. In this study, we tested the hypothesis that decreased fatty acid oxidation and increased lipid accumulation in the failing RV is driven, in part, by a relative carnitine deficiency. We then tested whether supplementation of l-carnitine can reverse lipotoxic RV failure through augmentation of fatty acid oxidation. In vivo in transgenic mice harboring a human BMPR2 mutation, l-carnitine supplementation reversed RV failure by increasing RV cardiac output, improving RV ejection fraction, and decreasing RV lipid accumulation through increased PPARγ expression and augmented fatty acid oxidation of long chain fatty acids. These findings were confirmed in a second model of pulmonary artery banding-induced RV dysfunction. In vitro, l-carnitine supplementation selectively increased fatty acid oxidation in mitochondria and decreased lipid accumulation through a Cpt1-dependent pathway. l-Carnitine supplementation improves right ventricular contractility in the stressed RV through augmentation of fatty acid oxidation and decreases lipid accumulation. Correction of carnitine deficiency through l-carnitine supplementation in PAH may reverse RV failure.

Natriuretic peptide receptor C contributes to disproportionate right ventricular hypertrophy in a rodent model of obesity-induced heart failure with preserved ejection fraction with pulmonary hypertension.

Heart failure with preserved ejection fraction (HFpEF) currently has no therapies that improve mortality. Right ventricular dysfunction and pulmonary hypertension are common in HFpEF, and thought to be driven by obesity and metabolic syndrome. Thus, we hypothesized that an animal model of obesity-induced HFpEF with pulmonary hypertension would provide insight into the pathogenesis of right ventricular failure in HFpEF. Two strains of mice, one susceptible (AKR) and one resistant (C3H) to obesity-induced HFpEF, were fed high fat (60% fat) or control diet for 0, 2, or 20 weeks and evaluated by cardiac catheterization and echocardiography for development of right ventricular dysfunction, pulmonary hypertension, and HFpEF. AKR, but not C3H, mice developed right ventricular dysfunction, pulmonary hypertension, and HFpEF. NPRC, which antagonizes beneficial natriuretic peptide signaling, was found in RNA sequencing to be the most differentially upregulated gene in the right ventricle, but not left ventricle or lung, of AKR mice that developed pulmonary hypertension and HFpEF. Overexpression of NPRC in H9C2 cells increased basal cell size and increased expression of hypertrophic genes, MYH7 and NPPA. In conclusion, we have shown that NPRC contributes to right ventricular modeling in obesity-induced pulmonary hypertension-HFpEF by increasing cardiomyocyte hypertrophy. NPRC may represent a promising therapeutic target for right ventricular dysfunction in pulmonary hypertension-HFpEF.

Psaudoaneurisma de la arteria hipogástrica izquierda, una causa extremadamente rara de sangrado puerperal tardío / Pseudoaneurysm of the left hypogastric artery, an extremely rare cause of late puerperal late puerperal bleeding

Resumen ANTECEDENTES: La hemorragia puerperal tardía implica una importante morbilidad y mortalidad que requiere una actuación urgente. Su causa es muy variada y requiere una cuidadosa valoración que permita detenerla, sin complicaciones. CASO CLÍNICO: Paciente de 42 años que a las cinco semanas posteriores a una cesárea acudió a Urgencias debido a un sangrado puerperal abundante. Enseguida de un legrado y exhaustiva revisión en el quirófano en la ecografía se identificó un área parauterina anecogénica sugerente de dilatación aneurismática comunicada con la cavidad uterina. El diagnóstico se estableció con base en la angiografía y se confirmó luego de la embolización mediante radiología intervencionista, sin contratiempos, y resolución del cuadro. La paciente se dio de alta del hospital en los siguientes dos días, con posteriores revisiones que se reportaron normales. CONCLUSIONES: La patología vascular debe formar parte del diagnóstico diferencial del sangrado puerperal tardío y, si se diagnostica adecuadamente, puede facilitar el procedimiento terapéutico mediante radiología intervencionista y evitar, así, otros tratamientos más invasivos.

Abstract BACKGROUND: Late puerperal hemorrhage is a major morbidity and mortality that requires urgent action. Its cause is very varied and requires careful assessment to stop it without complications. CLINICAL CASE: A 42-year-old woman came to the emergency department five weeks after cesarean section for heavy puerperal bleeding. After curettage and thorough examination in the operating room, ultrasound identified an anechogenic parauterine area suggestive of aneurysmal dilatation in communication with the uterine cavity. The diagnosis was established based on angiography and confirmed after embolization by interventional radiology, without mishap, and resolution of the picture. The patient was discharged in two days, with subsequent revisions reported as normal. CONCLUSIONS: Vascular pathology should be part of the differential diagnosis of late puerperal hemorrhage and, if properly diagnosed, may facilitate the therapeutic procedure by interventional radiology and thus avoid other more invasive treatments.

Composition, phase behavior and thermal stability of natural edible fat from rambutan (Nephelium lappaceum L.) seed.

In this paper, the chemical composition, the main physicochemical properties, phase behavior and thermal stability of rambutan (Nephelium lappaceum L.) seed fat were studied. These results showed that the almond-like decorticated seed represents 6.1% of the wet weight fruit and is: 1.22% ash, 7.80% protein, 11.6% crude fiber, 46% carbohydrates, and 33.4% fat (d.b.). The main fatty acids in the drupe fat were 40.3% oleic, 34.5% arachidic, 6.1% palmitic, 7.1% stearic, 6.3% gondoic, and 2.9% behenic; the refraction, saponification and iodine values were 1.468, 186, and 47.0, respectively. The phase behavior analysis showed relatively simple crystallization and melting profiles: crystallization showed three well-differentiated groups of triglycerides around maximum peaks at +30.8, +15.6 and -18.1 degrees C; the fat-melting curve had a range between -14.5 and +51.8 degrees C with a fusion enthalpy of 124.3 J/g. The thermal stability analyzed in an inert atmosphere of N(2) and in a normal oxidizing atmosphere, showed that in the latter, fat decomposition begins at 237.3 degrees C and concludes at 529 degrees C, with three stages of decomposition. According to these results, rambutan seed fat has physicochemical and thermal characteristics that may become interesting for specific applications in several segments of the food industry.