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.

Abstract-Aerobic exercise training (ET) lowers hypertension and improves patient outcomes in cardiovascular disease.The mechanisms of these effects are largely unknown. We hypothesized that ET modulates microRNAs (miRNAs) involved in vascularization. miRNA-16 regulates the expression of vascular endothelial growth factor and antiapoptotic protein Bcl-2. miRNA-21 targets Bcl-2. miRNA-126 functions by repressing regulators of the vascular endothelial growth factor pathway. We investigated whether miRNA-16, -21 and -126 are modulated in hypertension and by ET. Twelve-week-old male spontaneously hypertensive rats (SHRs; nϭ14) and Wistar Kyoto (WKY; nϭ14) rats were assigned to 4 groups: SHRs, trained SHRs (SHR-T), Wistar Kyoto rats, and trained Wistar Kyoto rats. ET consisted of 10 weeks of swimming. ET reduced blood pressure and heart rate in SHR-Ts. ET repaired the slow-to-fast fiber type transition in soleus muscle and the capillary rarefaction in SHR-Ts. Soleus miRNA-16 and -21 levels increased in SHRs paralleled with a decrease of 48% and 25% in vascular endothelial growth factor and Bcl-2 protein levels, respectively. Hypertension increased Bad and decreased Bcl-x and endothelial NO synthase levels and lowered p-Bad ser112 :Bad ratio. ET in SHR-Ts reduced miRNA-16 and -21 levels and elevated vascular endothelial growth factor and Bcl-2 levels. ET restored soleus endothelial NO synthase levels plus proapoptotic and antiapoptotic mediators in SHR-Ts, indicating that the balance between angiogenic and apoptotic factors may prevent microvascular abnormalities in hypertension. miRNA-126 levels were reduced in SHRs with an increase of 51% in phosphoinositol-3 kinase regulatory subunit 2 expression but normalized in SHR-Ts. Our data show that ET promoted peripheral revascularization in hypertension, which could be associated with regulation of select miRNAs, suggesting a mechanism for its potential therapeutic application in vascular diseases. A erobic exercise training (ET) is an established, nonpharmacological tool for prevention and treatment of hypertension, involving a decrease in the incidence of cardiovascular events. 1-3 ET improves endothelial function, counteracts microvascular rarefaction, and decreases blood pressure in hypertension. [1][2][3] However, the molecular mechanisms underlying these effects by ET in hypertension are poorly understood. Endothelial microRNAs (miRNAs) are potential therapeutic targets for tackling capillary rarefaction and defective angiogenesis in hypertension. 4 We hypothesized that ET modulates specific angiogenesis-related miRNAs in hypertension.miRNA profiles of endothelial cells have been reported and several highly expressed miRNAs identified with angiogenic factors as putative mRNA targets 130a,, according to prediction algorithms. [5][6][7]

In order to verify the effects of heat and exercise acclimation (HA) on resting and exercise-induced expression of plasma and leukocyte heat shock protein 72 (Hsp72) in humans, nine healthy young male volunteers (25.0± 0.7 years; 80.5±2.0 kg; 180±2 cm, mean ± SE) exercised for 60 min in a hot, dry environment (40±0°C and 45±0% relative humidity) for 11 days. The protocol consisted of running on a treadmill using a controlled hyperthermia technique in which the work rate was adjusted to elevate the rectal temperature by 1°C in 30 min and maintain it elevated for another 30 min. Before and after the HA, the volunteers performed a heat stress test (HST) at 50% of their individual maximal power output for 90 min in the same environment. Blood was drawn before (REST), immediately after (POST) and 1 h after (1 h POST) HST, and plasma and leukocytes were separated and stored.