Leucine-rich repeat containing 10 (LRRC10) is a cardiac-specific protein exclusively expressed in embryonic and adult cardiomyocytes. However, the role of LRRC10 in mammalian cardiac physiology remains unknown. To determine if LRRC10 is critical for cardiac function, Lrrc10-null (Lrrc10−/−) mice were analyzed. Lrrc10− /− mice exhibit prenatal systolic dysfunction and dilated cardiomyopathy in postnatal life. Importantly, Lrrc10−/− mice have diminished cardiac performance in utero, prior to ventricular dilation observed in young adults. We demonstrate that LRRC10 endogenously interacts with α-actinin and α-actin in the heart and all actin isoforms in vitro. Gene expression profiling of embryonic Lrrc10−/− hearts identified pathways and transcripts involved in regulation of the actin cytoskeleton to be significantly upregulated, implicating dysregulation of the actin cytoskeleton as an early defective molecular signal in the absence of LRRC10. In contrast, microarray analyses of adult Lrrc10−/− hearts identified upregulation of oxidative phosphorylation and cardiac muscle contraction pathways during the progression of dilated cardiomyopathy. Analyses of hypertrophic signal transduction pathways indicate increased active forms of Akt and PKCε in adult Lrrc10−/− hearts. Taken together, our data demonstrate that LRRC10 is essential for proper mammalian cardiac function. We identify Lrrc10 as a novel dilated cardiomyopathy candidate gene and the Lrrc10−/− mouse model as a unique system to investigate pediatric cardiomyopathy.

Alzheimer's disease is cytopathologically characterized by loss of synapses and neurons, neuritic amyloid plaques consisting of ␤-amyloid (A␤) peptides, and neurofibrillary tangles consisting of hyperphosphorylated tau protein in susceptible brain regions. A␤, which triggers a cascade of pathogenic events including tau phosphorylation and neuronal excitotoxicity, is proteolytically derived from ␤-amyloid precursor protein (APP); the pathological and physiological functions of APP, however, remain undefined. Here we demonstrate that the level of tau phosphorylation in cells and brains deficient in APP is significantly higher than that in wild-type controls, resulting from activation of cyclin-dependent kinase 5 (CDK5) but not glycogen synthase kinase 3, the two major tau kinases. In addition, we show that overexpression of APP or its non-amyloidogenic homolog amyloid precursor-like protein 1 suppresses both basal and stress-induced CDK5 activation. The ectodomain of APP, sAPP␣, is responsible for inhibiting CDK5 activation. Furthermore, neurons derived from APP-deficient mice exhibit reduced metabolism and survival rates and are more susceptible to excitotoxic glutamateinduced apoptosis. These neurons also manifest significant defects in neurite outgrowth compared with neurons from the wild-type littermates. The observed neuronal excitotoxicity/apoptosis is mediated through a mechanism involving CDK5 activation. Our study defines a novel neuroprotective function for APP in preventing tau hyperphosphorylation via suppressing overactivation of CDK5. We suggest that CDK5 activation, through a calcium/calpain/p25 pathway, plays a key role in neuronal excitotoxicity and represents an underlying mechanism for the physiological functions of APP.

Brody MJ, Feng L, Grimes AC, Hacker TA, Olson TM, Kamp TJ, Balijepalli RC, Lee Y. LRRC10 is required to maintain cardiac function in response to pressure overload. Am J Physiol Heart Circ Physiol 310: H269 -H278, 2016. First published November 25, 2015 doi:10.1152/ajpheart.00717.2014.-We previously reported that the cardiomyocyte-specific leucine-rich repeat containing protein (LRRC)10 has critical functions in the mammalian heart. In the present study, we tested the role of LRRC10 in the response of the heart to biomechanical stress by performing transverse aortic constriction on Lrrc10-null (Lrrc10 Ϫ/Ϫ ) mice. Mild pressure overload induced severe cardiac dysfunction and ventricular dilation in Lrrc10 Ϫ/Ϫ mice compared with control mice. In addition to dilation and cardiomyopathy, Lrrc10 Ϫ/Ϫ mice showed a pronounced increase in heart weight with pressure overload stimulation and a more dramatic loss of cardiac ventricular performance, collectively suggesting that the absence of LRRC10 renders the heart more disease prone with greater hypertrophy and structural remodeling, although rates of cardiac fibrosis and myocyte dropout were not different from control mice. Lrrc10 Ϫ/Ϫ cardiomyocytes also exhibited reduced contractility in response to ␤-adrenergic stimulation, consistent with loss of cardiac ventricular performance after pressure overload. We have previously shown that LRRC10 interacts with actin in the heart. Here, we show that His 150 of LRRC10 was required for an interaction with actin, and this interaction was reduced after pressure overload, suggesting an integral role for LRRC10 in the response of the heart to mechanical stress. Importantly, these experiments demonstrated that LRRC10 is required to maintain cardiac performance in response to pressure overload and suggest that dysregulated expression or mutation of LRRC10 may greatly sensitize human patients to more severe cardiac disease in conditions such as chronic hypertension or aortic stenosis. CARDIOMYOCYTE HYPERTROPHY in response to extracellular stimuli, such as neurohumoral or growth factor stimulation of membrane-bound receptors (13, 23, 44), or in response to mechanical stretch or strain that is sensed by mechanosensory machinery embedded in the Z-disc cytoskeleton, and sarcolemma (25, 38, 49). At the whole organ level, the heart undergoes hypertrophy as an adaptive mechanism to maintain cardiac output and reduce ventricular wall stress (20,23,38). While initially beneficial, prolonged cardiac hypertrophy becomes maladaptive and progresses to cardiac dilation, decompensation, heart failure, and/or sudden death (20,23,38). Cardiac hypertrophy can be induced by a number of cardiovascular diseases, such as myocardial infarction or chronic hypertension (23, 37). Indeed, high blood pressure is a common precursor to heart disease, particularly in the United States, where chronic hypertension is widespread (18,21,42). Despite increased awareness and treatment of hypertension, recent epidemiological studies have suggested that its prevalence con...

Objectives: We investigated the clinical outcome of stenting of unprotected left main coronary artery (LMCA). Methods: We studied 164 patients with nonbifurcated LMCA lesions (group A) and 96 patients with distal bifurcated lesions (group B). Results: Clinical follow-up was available in 100%. Angiographic follow-up was 87.3% in group A and 86% in group B (p = 0.922). There were significant differences in major adverse cardiac events at 1 (p = 0.014) and 2 years (p = 0.002) between group B (19.8%, 25.0%) and group A (9.1%, 10.4%), mainly due to increased target-vessel revascularization (16.7, 21.9% in group B vs. 6.1, 7.3% in group A, p = 0.006 and 0.001, respectively). The double-stent technique was associated with worse outcomes at 1 year in group B compared to group A. Bifurcation lesions (HR 3.42, 95% CI 1.34–5.61, p = 0.001), diabetes (HR 2.68, 95% CI 2.01–12.11, p = 0.015), three-vessel disease (HR 0.83, 95% CI 0.27–0.96, p = 0.001), incomplete revascularization (HR 0.15, 95% CI 0.11–0.35, p = 0.001) and stent diameter (HR 5.05, 95% CI 2.71–10.01, p = 0.03) were the independent factors of major adverse cardiac events in the whole patient cohort. Conclusion: Stenting unprotected distal bifurcated LMCA was associated with unfavorable results when compared to stenting other LMCA lesions.

The effect of selenium compounds on extracellular redox modulating capacity was studied in murine macrophage RAW 264.7 cells and differentiated human THP-1 monocytes. The arylselenium compounds benzeneselenol (PhSeH), dibenzyl diselenide (DBDSe), diphenyl diselenide (DPDSe), and ebselen were capable of inducing extracellular cysteine accumulation via a cystine- and glucose-dependent process. Extracellular cysteine production was dose-dependently inhibited by glutamate, an inhibitor of cystine/glutamate antiporter (Xc(-) transporter), supporting the involvement of Xc(-) transporter for cystine uptake in the above process. These arylselenium compounds also induced cellular thioredoxin reductase (TrxR) expression, particularly at the exofacial surface of cells. TrxR1 knockdown using small interfering RNA attenuated TrxR increases and cysteine efflux induced in cells by DPDSe. Sodium selenite (Na2SeO3), selenomethionine (SeMet), seleno-l-cystine (SeCySS), and Se-methylselenocysteine (MeSeCys) did not have these effects on macrophages under the same treatment conditions. The effects of organoselenium compounds on extracellular redox may contribute to the known, but inadequately understood, biological effects of selenium compounds.