Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression

Abstract

Schwartz, Faina, Arvi Duka, Irena Duka, Jing Cui, and Haralambos Gavras. Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression. Am J Physiol Heart Circ Physiol 287: H1957-H1966, 2004. First published July 8, 2004 doi:10.1152/ajpheart.00568.2004.-Although the central role of ANG II in cardiovascular homeostasis is well appreciated, the molecular circuitry of its many actions is not completely understood. With the use of serial analysis of gene expression to assess global transcriptional changes in the heart of mice after continuous 7-day ANG II administration, we identified patterns of gene expression indicative of cardiac remodeling, including coordinate regulation of genes previously described in a context of processes associated with hypertrophy and fibrosis. In addition, we discovered several novel ANG II targets, including characterized genes of known function, recently annotated genes of unknown function, and the putative genes not yet present in current databases. The serial analysis of gene expression approach to assess the role of ANG II presented in this report provides new venues for inquiries into ANG II-mediated cardiac function.genome-wide transcriptional profiling; hypertension; cardiac remodeling; hypertrophy; fibrosis THE KEY ROLE of ANG II in cardiovascular homeostasis is well documented. Although initially known for its vasoconstrictive action, the adverse effects of ANG II elevation on the heart independent of its hemodynamic influence were recognized in the early 1970s (7, 16), and the cardioprotective outcomes of the pharmacological interventions that either prevent the ANG II formation from the inactive angiotensinogen precursor (14) or inhibit its interaction with specific receptors (15, 48) are now well appreciated in clinical practice (6,13,17).Experimental animal studies have shown that ANG II administration can cause multifocal myocardial lesions (16, 47), and, via ANG II type 1 receptors, directly induce cardiac remodeling that involves myocyte hypertrophy (9, 25), fibroblast proliferation, and subsequent fibrosis (47), thus leading to the development of pathological cardiac hypertrophy and, ultimately, heart failure. Both in vivo and in vitro studies revealed that the ANG II effects in the heart are accompanied by changes in gene expression in the cardiac myocytes, fibroblasts, and endothelial cells (24). While the queries of selected ANG II targets supplied important information on several molecular pathways underlying the physiological and pathophysiological actions of ANG II, an all-inclusive view is provided by the genome-wide transcriptional profiling that offers an opportunity to connect separate pieces of the puzzle through the identification of the new players not intuitively obvious from our present understanding of physiology. Thus simultaneous evaluation of 4,000 genes by the use of microarray technology to query the quantitative changes in left ventricular RNA in response to ANG II-induced progression, and, subsequently, regre...

Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation

“…These results are consistent with recent reports of Cx43 downregulation and dephosphorylation in heart failure (1, 2). ANG II is known to affect transcription of multiple genes (45), possibly explaining the mRNA changes. Nevertheless, the origin of the chamberspecific regulation of connexins is unclear.…”

Cardioprotective properties of bradykinin: role of the B2 receptor

“…62 More recently, we have found that Ang II in vivo and in vitro stimulates gene overexpression of various vasoactive factors, including the B 1 R and B 2 R genes 53 as well as a novel gene, the cardiomyopathy-associated 3, also known as myomaxin and recently renamed Xirp2. [63][64][65] Although this gene's product remains unknown, its contribution to ischemic cardiomyopathy is crucial, as shown by studies in genetically engineered mice. 65 Interestingly, concurrent inhibition of the AT 1 receptor of Ang II with losartan can abolish the BK receptor upregulation.…”

Effect of Insulin and Losartan on Modulation of Insulin-Like Growth Factor 1 Receptor at Heart Level in Diabetic Rats

“…In the heart, it acts in both endocrine and paracrine fashions to regulate contractility, impulse propagation, remodeling, growth, and apoptosis [12]. Ang II has two major receptor subtypes, the AT 1 -R and the AT 2 -R, where CM are the major sites for these receptors expression [14,15]. The AT 1 -R mediates the classical functions of Ang II in the heart tissue, such as vasoconstriction and blood pressure elevation, mainly through the stimulation of phospholipase C, the mobilization of Ca 2+ and the phosphorylation of MAPK [15].…”

“…Ang II has two major receptor subtypes, the AT 1 -R and the AT 2 -R, where CM are the major sites for these receptors expression [14,15]. The AT 1 -R mediates the classical functions of Ang II in the heart tissue, such as vasoconstriction and blood pressure elevation, mainly through the stimulation of phospholipase C, the mobilization of Ca 2+ and the phosphorylation of MAPK [15]. The AT 2 -R seems to act as a sustainable repressor of AT 1 -R signaling pathway [14,16].…”