Rabbit Anti-Human AHSA1 Polyclonal Antibody

Coronary microvascular dysfunction predicts and may be a proximate cause of cardiac dysfunction and mortality in diabetes; however, few effective treatments exist for these conditions. We recently demonstrated that mineralocorticoid receptor (MR) antagonism reversed cardiovascular dysfunction in early-stage obesity/insulin resistance. The mechanisms underlying this benefit of MR antagonism and its relevance in the setting of longterm obesity complications like diabetes; however, remain unclear. Thus, the present study evaluated the impact of MR antagonism on diabetes-related coronary dysfunction and defines the MR-dependent vascular transcriptome in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat recapitulating later stages of human diabetes. OLETF rats were treated with spironolactone (Sp) and compared to untreated OLETF and lean Long-Evans Tokushima Otsuka rats. Sp treatment attenuated diabetes-associated adipose and cardiac inflammation/fibrosis and improved coronary endothelium-dependent vasodilation but did not alter enhanced coronary vasoconstriction, blood pressure, or metabolic parameters in OLETF rats. Further mechanistic studies using RNA deep sequencing of OLETF rat aortas revealed 157 differentially expressed genes following Sp including upregulation of genes involved in the molecular regulation of nitric oxide bioavailability (Hsp90ab1, Ahsa1, Ahsa2) as well as novel changes in am adrenergic receptors (Adrald), cyclooxygenase-2 (Ptgs2), and modulatory factors of these pathways (Ackr3, Acsl4). Further, Ingenuity Pathway Analysis predicted inhibition of upstream inflammatory regulators by Sp and inhibition of 'migration of endothelial cells', 'differentiation of smooth muscle', and 'angiogenesis' biological functions by Sp in diabetes. Thus, this study is the first to define the MR-dependent vascular transcriptome underlying treatment of diabetes-related coronary microvascular dysfunction by Sp.

The severity of most human birth defects is highly variable. Our ability to diagnose, treat and prevent defects relies on our understanding of this variability. Mutation of the transcription factor GATA3 in humans causes the highly variable hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome. Although named for a triad of defects, individuals with HDR can also exhibit craniofacial defects. Through a forward genetic screen for craniofacial mutants, we isolated a zebrafish mutant in which the first cysteine of the second zinc finger of Gata3 is mutated. Because mutation of the homologous cysteine causes HDR in humans, these zebrafish mutants could be a quick and effective animal model for understanding the role of gata3 in the HDR disease spectrum. We demonstrate that, unexpectedly, the chaperone proteins Ahsa1 and Hsp90 promote severe craniofacial phenotypes in our zebrafish model of HDR syndrome. The strengths of the zebrafish system, including rapid development, genetic tractability and live imaging, make this an important model for variability.