Aerobic exercise training leads to a physiological, non pathological left ventricular hypertrophy (LVH); however, the underlying biochemical and molecular mechanisms of physiological LVH are unknown. The role of microRNAs regulating the classic and the novel cardiac renin angiotensin system (RAS) was studied in trained rats assigned to three groups: sedentary, swimming trained with protocol 1 (T1: moderate volume training) and protocol 2 (T2: high volume training). Cardiac Ang I levels, ACE activity and protein expression, as well as Ang II levels were lower in T1 and T2, however AT1 mRNA levels (69% in T1 and 99% in T2) and protein expression (240% in T1 and 300% in T2) increased after training. AT2 receptor mRNA levels (220%) and protein expression (332%) were shown to be increased in T2. In addition, T1 and T2 were shown to increase ACE2 activity and protein expression, and Ang (1–7) levels in the heart. Exercise increased microRNA-27a and 27b, targeting ACE and decreasing microRNA-143 targeting ACE2 in the heart. LVH induced by aerobic training involves microRNAs regulation and an increase in cardiac AT1 receptor without the participation of Ang II. Parallel to this, increase in ACE2, Ang (1–7) and AT2 receptor in the heart by exercise suggests that this non classic cardiac RAS counteracts the classic cardiac RAS. These findings are consistent with a model in which exercise may induce LVH, at least in part, altering the expression of specific microRNAs targeting RAS genes. Together these effects might provide the additional aerobic capacity required by the exercised heart.

MiRNAs regulate cardiac development, hypertrophy, and angiogenesis, but their role in cardiac hypertrophy (CH) induced by aerobic training has not previously been studied. Aerobic training promotes physiological CH preserving cardiac function. This study assessed involvement of miRNAs-29 in CH of trained rats. Female Wistar rats (n ϭ 7/group) were randomized into three groups: sedentary (S), training 1 (T1), training 2 (T2). T1: swimming sessions of 60 min/5 days/wk/10 wk. T2: similar to T1 until 8th wk. On the 9th wk rats swam 2ϫ/day, and on the 10th wk 3ϫ/day. MiRNAs analysis was performed by miRNA microarray and confirmed by real-time PCR. We assessed: markers of training, CH by ratio of left ventricle (LV) weight/body wt and cardiomyocytes diameter, pathological markers of CH (ANF, skeletal ␣-actin, ␣/␤-MHC), collagen I and III (COLIAI and COLIIIAI) by real-time PCR, protein collagen by hydroxyproline (OH-proline) concentration, CF and CH by echocardiography. Training improved aerobic capacity and induced CH. MiRNAs-1, 133a, and 133b were downregulated as observed in pathological CH, however, without pathological markers. MiRNA-29c expression increased in T1 (52%) and T2 (123%), correlated with a decrease in COLIAI and COLIIIAI expression in T1 (27%, 38%) and T2 (33%, 48%), respectively. MiRNA-29c was inversely correlated to OH-proline concentration (r ϭ 0.61, P Ͻ 0.05). The E/A ratio increased in T2, indicating improved LV compliance. Thus, these results show that aerobic training increase miR-29 expression and decreased collagen gene expression and concentration in the heart, which is relevant to the improved LV compliance and beneficial cardiac effects, associated with aerobic high performance training. cardiac hypertrophy; collagen; molecular markers; swimming training; physiological cardiac hypertrophy; diastolic function microRNAs (miRNAs) are recognized as a new class of gene expression regulators, consisting of short RNAs, singlestranded, that do not synthesize proteins.MiRNAs are currently potential therapeutic targets and biomarkers in cardiovascular research of various physiological and pathological processes (2,3,(33)(34)(35)(36)(37)40). The action of miRNAs occurs at the posttranscriptional level. MiRNAs negatively regulate the expression of their target genes by coupling to the 3=-untranslated regions (3=-UTR) of mRNA expressed by the target gene (direct modulation) or in the 3=-UTR of mRNA related with the expression of target gene (indirect modulation), which represses its translation into protein (18,19).There are several studies involving miRNAs in pathological cardiac hypertrophy (CH) (2, 3, 29, 35, 36). MiRNAs-1, 133a, and 133b are the best known and highly expressed in heart (36) and already have several targets genes validated, as transcription factors, proteins involved in cellular growth and division, rearrangement of myofibrils and cardiac contractility (34). Carè et al. (2) reported that the decreased expression of miRNA-1 and 133 in vivo and in vitro has a critical role in hypertro...

We evaluated the effects of swimming and anabolic steroids (AS) on ventricular function, collagen synthesis, and the local renin-angiotensin system in rats. Male Wistar rats were randomized into control (C), steroid (S; nandrolone decanoate; 5 mg/kg sc, 2x/wk), steroid + losartan (SL; 20 mg.kg(-1).day(-1)), trained (T), trained + steroid (T+S), and trained + steroid + losartan (T+SL; n = 14/group) groups. Swimming was performed 5 times/wk for 10 wk. Serum testosterone increased in S and T+S. Resting heart rate was lower in T and T+S. Percent change in left ventricular (LV) weight-to-body weight ratio increased in S, T, and T+S. LV systolic pressure declined in S and T+S. LV contractility increased in T (P < 0.05). LV relaxation increased in T (P < 0.05). It was significantly lower in T+S compared with C. Collagen volumetric fraction (CVF) and hydroxyproline were higher in S and T+S than in C and T (P < 0.05), and the CVF and LV hypertrophy were prevented by losartan treatment. LV-ANG I-converting enzyme activity increased (28%) in the S group (33%), and type III collagen synthesis increased (56%) in T+S but not in T group. A positive correlation existed between LV-ANG I-converting enzyme activity and collagen type III expression (r(2) = 0.88; P < 0.05, for all groups). The ANG II and angiotensin type 1a receptor expression increased in the S and T+S groups but not in T group. Supraphysiological doses of AS exacerbated the cardiac hypertrophy in exercise-trained rats. Exercise training associated with AS induces maladaptive remodeling and further deterioration in cardiac performance. Exercise training associated with AS causes loss of the beneficial effects in LV function induced by exercising. These results suggest that aerobic exercise plus AS increases cardiac collagen content associated with activation of the local renin-angiotensin system.

Aerobic exercise-induced cardiac hypertrophy (CH) is a physiological response involving accurate orchestration of gene and protein expression of contractile and metabolic components. The microRNAs: , and are each encoded by a myosin gene and thus are also known as 'MyomiRs', regulating several mRNA targets that in turn regulate CH and metabolic pathways. To understand the role of myomiRs in the fine-tuning of cardiac myosin heavy chain (MHC) isoform expression by exercise training-induced physiological hypertrophy, Wistar rats were subjected to two different swim training protocols. We observed that high-volume swim training (T2), improved cardiac diastolic function, induced CH and decreased the expression of and Consequently, the increased expression of their targets, sex determining region y-related transcription factor 6 (Sox6), Med13, Purβ, specificity proteins (Sp)/Krüppel-like transcription factor 3 (SP3) and HP1β (heterochromatin protein 1β) was more prominent in T2, thus converging to modulate cardiac metabolic and contractile adaptation by exercise training, with an improvement in the α-MHC/β-MHC ratio, bypassing the increase in PPARβ and histone deacetylase (HDAC) class I and II regulation. Altogether, we conclude that high-volume swim training finely assures physiological cardiac remodelling by epigenetic regulation of myomiRs, because inhibition of and increases the expression of their target proteins and stimulates the interaction among metabolic, contractile and epigenetic genes.