Androgen Receptor Gene Knockout Male Mice Exhibit Impaired Cardiac Growth and Exacerbation of Angiotensin II-induced Cardiac Fibrosis

Abstract

Androgen has anabolic effects on cardiac myocytes and has been shown to enhance left ventricular enlargement and function. However, the physiological and patho-physiological roles of androgen in cardiac growth and cardiac stress-induced remodeling remains unclear. We aimed to clarify whether the androgen-nuclear androgen receptor (AR) system contributes to the cardiac growth and angiotensin II (Ang II)-stimulated cardiac remodeling by using systemic AR-null male mice. AR knock-out (ARKO) male mice, at 25 weeks of age, and age-matched wild-type (WT) male mice were treated with or without Ang II stimulation (2.0 mg/kg/day) for 2 weeks. ARKO mice with or without Ang II stimulation showed a significant reduction in the heart-to-body weight ratio compared with those of WT mice. In addition, echocardiographic analysis demonstrated impairments of both the concentric hypertrophic response and left ventricular function in Ang II-stimulated ARKO mice. Western blot analysis of the myocardium revealed that activation of extracellular signal-regulated kinases (ERK) 1/2 and ERK5 by Ang II stimulation were lower in ARKO mice than those of WT mice. Ang II stimulation caused more prominent cardiac fibrosis in ARKO mice than in WT mice with enhanced expression of types I and III collagen and transforming growth factor-␤1 genes and with increased Smad2 activation. These results suggest that, in male mice, the androgen-AR system participates in normal cardiac growth and modulates cardiac adaptive hypertrophy and fibrosis during the process of cardiac remodeling under hypertrophic stress.Androgen exerts a variety of biological effects in many target organs, including male genitalia, brain, and skeletal tissues (1, 2). Most of these actions are mediated through the transcriptional control of particular sets of target genes by the nuclear androgen receptor (AR).1 AR is a ligand-inducible transcription factor that belongs to the nuclear receptor superfamily (3, 4). Upon hormone binding, AR is translocated from the cytosol into the nucleus where it binds specific promoter elements. A number of coregulators and/or coregulator complexes are then recruited to AR, which then activates or represses the transcription of various target genes (2, 3, 5-7). To clarify the physiological function of androgen via AR transcriptional regulation, we generated AR knock-out (ARKO) mice by means of the Cre-loxP system and have reported that ARKO male mice manifest late-onset obesity (8), high turnover osteopenia (9), and impaired brain masculinization (10).In addition to the classic target tissues of androgens, the AR gene is also expressed in mammalian cardiomyocytes, suggesting that androgens may play a role in the heart (11). In fact, Marsh and colleagues (11) have shown that androgens produce cardiac hypertrophy by a direct, receptor-specific mechanism. They also revealed that androgens regulate functional expression of an L-type calcium channel in isolated rat ventricular myocytes, leading to a modulation of cardiac performance in males (12). Li et a...

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Cardiac-specific Deletion of LKB1 Leads to Hypertrophy and Dysfunction

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“…cDNA Synthesis and Quantitative Real Time PCR-Atria and ventricular tissue were homogenized in TRIzol reagent, and RNA was extracted as described previously (17). A QuantiTect Reverse Transcription kit (Qiagen, Valencia, CA) was used to synthesize cDNA, and PCR was performed using the iCycler iQ Real Time PCR Detection Systems (Bio-Rad) with SYBR Green dye (19).…”

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