Shifting Paradigm from Gene Expressions to Pathways Reveals Physiological Mechanisms in Blood Pressure Control in Causation.

Genetics for blood pressure (BP) in human and animals has been partitioned into two separate specialties. However, this divide is mechanistically-misleading. BP physiology is mechanistically participated by products of quantitative trait loci (QTLs).

Genetics of Normotension Preventing Hypertension Leads to a Novel Physiological Paradigm.

Possessing blood pressure in normal ranges is considered healthy, and does not warrant medical attention for obvious clinical reasons. However, to realize normotension and then maintain it even when confronted with a hypertensive threat must have its biological 'shield of armour'. While sensitivity to hypertension has been widely recognized and studied, inherent mechanisms that enable a physiological resistance to hypertension to occur have received little attention.

Conserved mammalian modularity of quantitative trait loci revealed human functional orthologs in blood pressure control.

Genome-wide association studies (GWAS) have routinely detected human quantitative trait loci (QTLs) for complex traits. Viewing that most GWAS single nucleotide polymorphisms (SNPs) are found in non-coding regions unrelated to the physiology of a polygenic trait of interest, a vital question to answer is whether or not any of these SNPs can functionally alter the phenotype with which it is associated. The study of blood pressure (BP) is a case in point.

Functional Captures of Multiple Human Quantitative Trait Loci Regulating Blood Pressure with the Use of Orthologs in Genetically Defined Rat Models.

Background: Most signals from human genome-wide association studies (GWAS) for blood pressure (BP) are single-nucleotide polymorphisms (SNPs). It was unknown if such SNPs can functionally affect BP. Because BP is similar between humans and rodents, unraveling basic mechanisms from rodents can reveal the same BP-modulating mechanisms in humans originating from their common ancestors while overcoming limitations in human epidemiology.

Modularity/non-cumulativity of quantitative trait loci on blood pressure.

Large numbers of quantitative trait loci (QTLs) for blood pressure (BP) exist and have long been thought to function by accumulating their individual miniscule effects. Recent experimental evidence in the functional biology of BP control has tested this intuitive assumption. A new paradigm has emerged that BP is biologically determined in modularity by multiple QTLs.

Biological convergence of three human and animal model quantitative trait loci for blood pressure.

Objectives: Blood pressure (BP) is comparable among different mammalian orders, despite their evolution divergence. Because of it, fundamental mechanisms should connect humans and rodents by their shared BP physiology. We hypothesized that similar quantitative trait loci (QTLs) function in both humans and rodents in controlling BP.

Functional Dosage of Muscarinic Cholinergic Receptor 3 Signalling, Not the Gene Dose, Determines Its Hypertension Pathogenesis.

Background: Multiple quantitative trait loci for blood pressure (BP) have been localized throughout human and rodent genomes. Few of them have been functionally identified especially in humans, and little is known about their pathogenic directionality when identified. We focused on Chrm3 encoding the muscarinic cholinergic receptor 3 (M3R) as the causal gene for C17QTL1 in the Dahl salt-sensitive rat model.

Novel Pathogenesis of Hypertension and Diastolic Dysfunction Caused by M3R (Muscarinic Cholinergic 3 Receptor) Signaling.

Multiple quantitative trait loci for blood pressure (BP) are localized in humans and rodent models. Model studies have not only produced human quantitative trait loci homologues but also provided unforeseen mechanistic insights into the function modality of quantitative trait loci actions. Presently, congenic knockins, gene-specific knockout, and in vitro and in vivo function studies were used in a rat model of polygenic hypertension, DSS (Dahl salt sensitive) rats.

Structural Insight into the Photochemistry of Split Green Fluorescent Proteins: A Unique Role for a His-Tag.

Oligohistidine affinity tags (His-tags) are commonly fused to proteins to aid in their purification via metal affinity chromatography. These His-tags are generally assumed to have minimal impact on the properties of the fusion protein, as they have no propensity to form ordered elements, and are small enough not to significantly affect the solubility or size. Here we report structures of two variants of truncated green fluorescent protein (GFP), i.

Retinoblastoma-associated protein 140 as a candidate for a novel etiological gene to hypertension.

Gene discovery in animal models may lead to the revelation of therapeutic targets for essential hypertension as well as mechanistic insights into blood pressure (BP) regulation. Our aim was to identify a disease-causing gene for a component of polygenic hypertension contrasting inbred hypertensive Dahl salt-sensitive (DSS) and normotensive Lewis rats. The chromosome segment harboring a quantitative trait locus (QTL), C16QTL, was first isolated from the rat genome via congenic strains.

Alterations in Fibronectin Type III Domain Containing 1 Protein Gene Are Associated with Hypertension.

Multiple quantitative trait loci (QTLs) for blood pressure (BP) have been detected in rat models of human polygenic hypertension. Great challenges confronting us include molecular identifications of individual QTLs. We first defined the chromosome region harboring C1QTL1 to a segment of 1.

Two candidate genes for two quantitative trait loci epistatically attenuate hypertension in a novel pathway.

Objectives: Multiple quantitative trait loci (QTLs) for blood pressure (BP) have been detected in rat models of human polygenic hypertension. They influence BP physiologically via epistatic modules. Little is known about the causal genes and virtually nothing is known on modularized mechanisms governing their regulatory connections.

Hypertension Suppression, Not a Cumulative Thrust of Quantitative Trait Loci, Predisposes Blood Pressure Homeostasis to Normotension.

Background: Genetics of high blood pressure (BP) has revealed causes of hypertension. The cause of normotension, however, is poorly understood. Inbred Lewis rats sustain normotension despite a genetic push in altering BP.

Genetic mechanisms of polygenic hypertension: fundamental insights from experimental models.

Essential hypertension is one of the most common disorders that underpin significant morbidity and mortality; however, underlying mechanisms remain elusive that either dictate the actions of individual quantitative trait loci (QTLs) or engineer the overall genetic architecture from them. Recent experimental evidence has unveiled that the genetic architecture determining blood pressure (BP) is assembled from QTL-building blocks by epistasis into regulatory hierarchies. BP, a polygenic and quantitative trait, is homeostasized via pathways participated by Mendelian constituents that operate distantly from end-phase physiological genes.

Genetics of systolic and diastolic heart failure.

Heart failure accounts for a significant portion of heart diseases. Molecular mechanisms gradually emerge that participate in pathways leading to left ventricular dysfunction in common systolic heart failure (SHF) and diastolic heart failure (DHF). A human genome-wide association study (GWAS) identified two markers for SHF and no GWAS on DHF has been documented.

Genetics of diastolic heart failure.

Heart failure explains a large portion of heart diseases. Molecular mechanisms determining cardiac function, by inference dysfunction in heart failure, are incompletely understood, especially in the common (or congestive) systolic (SHF) and diastolic heart failure (DHF). Limited genome-wide association studies (GWASs) in humans are reported on SHF and no GWAS has been performed on DHF.

Mechanism of ubiquitin ligation and lysine prioritization by a HECT E3.

Ubiquitination by HECT E3 enzymes regulates myriad processes, including tumor suppression, transcription, protein trafficking, and degradation. HECT E3s use a two-step mechanism to ligate ubiquitin to target proteins. The first step is guided by interactions between the catalytic HECT domain and the E2∼ubiquitin intermediate, which promote formation of a transient, thioester-bonded HECT∼ubiquitin intermediate.

Modularization and epistatic hierarchy determine homeostatic actions of multiple blood pressure quantitative trait loci.

Hypertension, the most frequently diagnosed clinical condition world-wide, predisposes individuals to morbidity and mortality, yet its underlying pathological etiologies are poorly understood. So far, a large number of quantitative trait loci (QTLs) have been identified in both humans and animal models, but how they function together in determining overall blood pressure (BP) in physiological settings is unknown. Here, we systematically and comprehensively performed pair-wise comparisons of individual QTLs to create a global picture of their functionality in an inbred rat model.

Unique quantitative trait loci in synergy permanently improve diastolic dysfunction.

Background: Diastolic dysfunction often precedes the onset of diastolic heart failure. We previously demonstrated that diastolic dysfunction and left ventricular hypertrophy (LVH) in Dahl salt-sensitive rats can be ameliorated by quantitative trait loci (QTLs).

Methods: We analyzed cardiac phenotypes of 2 "single" congenic strains, C10S.

Combining distinctive and novel loci doubles BP reduction, reverses diastolic dysfunction and mitigates LV hypertrophy.

Objectives: Diastolic dysfunction often represents the onset of diastolic heart failure (DHF). We previously showed in principle that diastolic function in Dahl salt-sensitive rats (DSS) can be genetically determined by quantitative trait loci (QTLs) that also modulate blood pressure (BP).

Methods: We analyzed cardiac phenotypes of four 'single' congenic strains by echocardiography, in which a specific DSS chromosome segment was replaced by its normotensive Lewis homologue.

Noncanonical E2 recruitment by the autophagy E1 revealed by Atg7-Atg3 and Atg7-Atg10 structures.

Core functions of autophagy are mediated by ubiquitin-like protein (UBL) cascades, in which a homodimeric E1 enzyme, Atg7, directs the UBLs Atg8 and Atg12 to their respective E2 enzymes, Atg3 and Atg10. Crystallographic and mutational analyses of yeast (Atg7-Atg3)(2) and (Atg7-Atg10)(2) complexes reveal noncanonical, multisite E1-E2 recognition in autophagy. Atg7's unique N-terminal domain recruits distinctive elements from the Atg3 and Atg10 'backsides'.

Novel genes as primary triggers for polygenic hypertension.

Objectives: The discovery of causative genes leading to hypertension in animal models can reveal new mechanistic insights into blood pressure (BP) regulations. Previously, we isolated segments that harbor BP quantitative trait loci (QTLs) on rat chromosome 10 as defined by congenic strains made from crosses of inbred hypertensive Dahl salt-sensitive (DSS) and normotensive Lewis rats. The aim of the current study was to identify hypertension-causing genes for each QTL.

Atg8 transfer from Atg7 to Atg3: a distinctive E1-E2 architecture and mechanism in the autophagy pathway.

Atg7 is a noncanonical, homodimeric E1 enzyme that interacts with the noncanonical E2 enzyme, Atg3, to mediate conjugation of the ubiquitin-like protein (UBL) Atg8 during autophagy. Here we report that the unique N-terminal domain of Atg7 (Atg7(NTD)) recruits a unique "flexible region" from Atg3 (Atg3(FR)). The structure of an Atg7(NTD)-Atg3(FR) complex reveals hydrophobic residues from Atg3 engaging a conserved groove in Atg7, important for Atg8 conjugation.

α-Kinase 2 is a novel candidate gene for inherited hypertension in Dahl rats.

Objectives: The interval harboring a quantitative trait locus for blood pressure (BP), C18QTL3, contains β-2 adrenergic receptor (Adrb2) and neural precursor cell expressed, developmentally downregulated 4-like (Nedd4l) genes. None of the other genes in the C18QTL3-residing interval is known to affect BP. The identification of C18QTL3 might uncover a brand new gene that could prosper into a novel diagnostic and/or therapeutic target for essential hypertension, if neither Adrb2 nor Nedd4l could be upheld as candidate genes.