Inflammation, Autoimmunity, and Hypertension: The Essential Role of Tissue Transglutaminase.
Inflammatory cytokines cause hypertension when introduced into animals. Additional evidence indicates that cytokines induce the production of autoantibodies that activate the AT1 angiotensin receptor (AT1R). Extensive evidence shows that these autoantibodies, termed AT1-AA, contribute to hypertension. We review here recent studies showing that cytokine-induced hypertension and AT1-AA production require the ubiquitous enzyme, tissue transglutaminase (TG2). We consider 3 mechanisms by which TG2 may contribute to hypertension. (i) One involves the posttranslational modification (PTM) of AT1Rs at a glutamine residue that is present in the epitope sequence (AFHYESQ) recognized by AT1-AA. (ii) Another mechanism by which TG2 may contribute to hypertension is by PTM of AT1Rs at glutamine 315. Modification at this glutamine prevents ubiquitination-dependent proteasome degradation and allows AT1Rs to accumulate. Increased AT1R abundance is likely to account for increased sensitivity to Ang II activation and in this way contribute to hypertension. (iii) The increased TG2 produced as a result of elevated inflammatory cytokines is likely to contribute to vascular stiffness by modification of intracellular contractile proteins or by crosslinking vascular proteins in the extracellular matrix. This process, termed inward remodeling, results in reduced vascular lumen, vascular stiffness, and increased blood pressure. Based on the literature reviewed here, we hypothesize that TG2 is an essential participant in cytokine-induced hypertension. From this perspective, selective TG2 inhibitors have the potential to be pharmacologic weapons in the fight against hypertension.
Department of Biochemistry and Molecular Biology, McGovern Medical School of the University of Texas at Houston, Houston, Texas, USA.
Chen
C
Liu
Department of Biochemistry and Molecular Biology, McGovern Medical School of the University of Texas at Houston, Houston, Texas, USA.
Rodney E
RE
Kellems
Department of Biochemistry and Molecular Biology, McGovern Medical School of the University of Texas at Houston, Houston, Texas, USA.
Yang
Y
Xia
D000328:Adult; D001327:Autoimmune Diseases / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D006973:Hypertension / Q000209:etiology* / Q000473:pathology*; D007249:Inflammation / Q000150:complications* / Q000473:pathology*; D011247:Pregnancy; D011503:Transglutaminases / Q000378:metabolism*
D016207:Cytokines; D011503:Transglutaminases
GPCR; angiotensin II type I receptor; autoimmunity; blood pressure; hypertension; inflammatory cytokines; rennin–angiotensin–aldosterone system; tissue transglutaminase; vascular stiffness