Functional Non‐Coding ncRNA in Vascular Epigenetics: Redox Editing and Structural Relations of Factors

OBJECTIVE From same genotypes, formation and remodeling of different vascular phenotypes result from coded genetic [Mendelian] and epigenetic [non‐Mendelian] reactions. These are subject to intrinsic and extrinsic environmental chance factors. Normal but also maladaptive blood and lymphatic vessel patterns may result from vasculo‐, angio‐, arterio‐ and lymph‐angiogenesis by complex interplay of many cells and factors [proteins, RNA, metal ions, environment]. The influence of environmental chemical redox [metabolic, hypoxic] and physical [mechanosensitive, shear stress] chance reactions on the main RNA transcript fraction [ncRNA] of activated cells and structural properties shared in factors were investigated as potential targets of therapy escaping consideration, so far. METHODS materials and stress factors on cells are in Ann. N.Y. Acad. Sci. 1137: 316–342, 2008. For search, angiotropin and microRNA‐126 [miR 126] structures were used. RESULTS Upon environmental chance reactions [stress, exercise, hypoxia], endothelial cells and macrophages form functional regulatory RNAs. miR 126 reported angiogenic is a 21n epigraphic split product without 5′ CUG 3′ motif of its Mendelian 85bp MIR126 gene. It has no modified bases. Angiotropin is a RNP angiomorphogen, sequenced as the first RNA mediator after isolation from extracellular fluids where it is active: By metal ions [Cu, Ca, Na, K], a Mendelian‐coded angiotropin‐related protein [ARP, S100‐A12] folds with a non‐Mendelian episcription product. This is a functional non‐coding 5′ end‐phosphorylated, edited, modified, redox‐ and metallo‐regulated angiotropin‐related small hairpin RNA [ARNA, 75n]. Its isoguanosine [crotonoside]/adenosine‐N1‐oxide of 151Da base family is from Fenton‐type redox‐OH*‐radical RNA chance modification with complexing copper ions. A metal ion‐structured 5′ CUG 3′ ‐hairpin loop of ARNA fits to folded ARP protein groove. In focus is on one hand: Mechanosensitive and other epigenetic regulator proteins of angiogenesis like ARP share defined conserved RNA‐affine homologous helix‐nucleating Mendelian consensus domains. On other hands, base sequences of 21n miR 126‐5p and phosphorylated 5′ ‐end of ARNA [75n] share ~80% base homology as common property. Further parts of ARNA show recombined fractals of 21n miR 126‐3p, the complementary RNA and 5′ CUG 3′ motif of its Mendelian 85bp MIR126 gene. CONCLUSIONS The results suggest novel mechanisms and therapeutic targets in vascular phenotype epigenetics: It is driven by new RNA sequence codes implementing redox editing with copper ions by modification of some adenosines to isoguanosine [crotonoside] via disproportionation of adenosine‐N1‐oxide. Although all are very different, epigraphic Mendelian and fractals of nonmendelian episcription factors share intimate structural relations. Angiotropin structure and function evaluated pregenomic 30 years ago now again shows up novel and unique from genome structure aspects: These let it rise again as intimate to the multifactorial nature of metal ions, proteins and regulatory RNA in algorithms [chance and necessity] of vascular epigenetics, translation of entangled cancer‐angiogenesis‐tolerance and many other adaptation reactions.