RESUMEN
The ability to produce apolipoprotein (apo) B-containing lipoproteins enables hepatocytes, enterocytes, and cardiomyocytes to export triglycerides. In this study, we examined secretion of apoB-containing lipoproteins from mouse kidney and its putative impact on triglyceride accumulation in the tubular epithelium. Mouse kidney expressed both the apoB and microsomal triglyceride transfer protein genes, which permit lipoprotein formation. To examine de novo lipoprotein secretion, kidneys from human apoB-transgenic mice were minced and placed in medium with (35)S-amino acids. Upon sucrose gradient ultracentrifugation of the labeled medium, fractions were analyzed by apoB immunoprecipitation. (35)S-Labeled apoB100 was recovered in approximately 1.03-1.04 g/ml lipoproteins (i.e. similar to the density of plasma low density lipoproteins). Immunohistochemistry of kidney sections suggested that apoB mainly is produced by tubular epithelial cells. ApoB expression in the kidney cortex was reduced approximately 90% in vivo by treating wild type mice with apoB-antisense locked nucleic acid oligonucleotide. Inhibition of apoB expression increased fasting-induced triglyceride accumulation in the kidney cortex by 20-25% (p = 0.008). Cholesterol stores were unaffected. Treatment with control oligonucleotides with 1 or 4 mismatching base pairs affected neither the triglyceride nor the cholesterol content of the kidney cortex. The results suggest that mammalian kidney secretes apoB100-containing lipoproteins. One biological effect may be to dampen excess storage of triglycerides in proximal tubule cells.
Asunto(s)
Apolipoproteínas B/fisiología , Colesterol/metabolismo , Riñón/metabolismo , Triglicéridos/metabolismo , Animales , Apolipoproteína B-100/genética , Apolipoproteína B-100/metabolismo , Western Blotting , Humanos , Riñón/citología , Lipoproteínas/genética , Lipoproteínas/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Oligonucleótidos Antisentido/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The electron-dense spherical granules found in the perinuclear region of atrial myocytes store and release both proatrial and probrain natriuretic peptides (proANP and proBNP, respectively). Mature ANP and BNP produce vasodilation and natriuresis and inhibit the renin-angiotensin and sympathetic nervous systems. Although neither ANP nor BNP is a-amidated, Peptidylglycine a-Amidating Monooxygenase (PAM), an integral membrane enzyme known to catalyze the a-amidation of peptidylglycine precursors, is the major atrial granule membrane protein. Selective deletion of PAM from cardiomyocytes impairs their ability to store proANP, resulting in an increase in proANP secretion. Exogenous expression of active or inactive PAM protein restores the ability of atrial myocytes to store proANP, leading to the suggestion that PAM functions as a cargo receptor for newly synthesized proANP.
RESUMEN
BACKGROUND: Prolongation of the QT interval on the electrocardiogram is clinically important due to the association with an increased risk of sudden cardiac death. A long QT interval may be genetically determined (congenital long QT syndrome) or be drug-induced long QT syndrome e.g. caused by pharmaceutical drugs and electrolyte imbalances. CASE SUMMARY: In this report, we describe the case a 54-year-old woman, who presented with syncope. At presentation, the QTc interval was markedly prolonged, and she was admitted for observation under telemetry. The following day the patient had experienced a near syncope during an episode of 18 s of Torsade de Pointes (TdP). At the time of TdP, the potassium level (3.4 mmol/L) was mildly reduced, and the ECG showed a QTc interval of 640 ms. In spite of correction of hypokalaemia and discontinuation of the possibly LQTS-inducing drug citalopram the QTc duration remained intermittently prolonged. A transthoracic echocardiogram and a recent coronary angiogram were normal. The patient received an implantable cardioverter-defibrillator. Subsequent genetic testing identified a heterozygous KCNE1 p.D85N (c.253G>A) variant, a known QT modifier with a population prevalence of 1.3%. DISCUSSION: We conclude that the combination of a commonly prescribed antidepressant, discrete hypokalaemia, and a common KCNE1 QT modifier may cause severe QTc prolongation and life-threatening arrhythmia.
Asunto(s)
Muerte Súbita Cardíaca , Pruebas Genéticas , Autopsia , Genómica , Humanos , Secuenciación del ExomaRESUMEN
Plasma B-type natriuretic peptide (BNP) and proBNP are established markers of cardiac dysfunction. Even though obesity increases the risk of cardiovascular disease, obese individuals have reduced plasma concentrations of natriuretic peptides. The underlying mechanism is not established. We used cultured cardiomyocytes and three different mouse models to examine the impact of obesity and cardiac lipid accumulation on cardiac natriuretic peptide expression. The cardiac ventricular expression of atrial natriuretic peptide (ANP) and BNP mRNA and ANP peptide was decreased 36-72% in obese ob/ob, db/db, and fat-fed C57BL/6 mice as compared with their respective controls. The db/db and ob/ob mice displayed impaired cardiac function, whereas the fat-fed mice had almost normal cardiac function. Moreover, the ventricular expression of hypertrophic genes (α- and ß-myosin heavy chain and α-actin) and natriuretic peptide receptor genes were not consistently altered by obesity across the three mouse models. In contrast, cardiac ventricular triglycerides were similarly increased by 60-115% in all three obese mouse models and incubation with oleic acid caused triglyceride accumulation and an approximately 35% (P < 0.005) depression of ANP mRNA expression in cultured HL-1 atrial myocytes. The data suggest that obesity and altered cardiac lipid metabolism are associated with reduced production of ANP and BNP in the cardiac ventricles in the setting of normal as well as impaired cardiac function.