Temporal changes in cardiac oxidative stress, inflammation and remodeling induced by exercise in hypertension: Role for local angiotensin II reduction

Exercise training reduces renin-angiotensin system (RAS) activation, decreases plasma and tissue oxidative stress and inflammation in hypertension. However, the temporal nature of these phenomena in response to exercise is unknown. We sought to determine in spontaneously hypertensive rats (SHR) and age-matched WKY controls the weekly effects of training on blood pressure (BP), plasma and left ventricle (LV) Ang II and Ang-(1–7) content (HPLC), LV oxidative stress (DHE staining), gene and protein expression (qPCR and WB) of pro-inflammatory cytokines, antioxidant enzymes and their consequence on hypertension-induced cardiac remodeling. SHR and WKY were submitted to aerobic training (T) or maintained sedentary (S) for 8 weeks; measurements were made at weeks 0, 1, 2, 4 and 8. Hypertension-induced cardiac hypertrophy was accompanied by acute plasma Ang II increase with amplified responses during the late phase of LV hypertrophy. Similar pattern was observed for oxidative stress markers, TNF alpha and interleukin-1β, associated with cardiomyocytes’ diameter enlargement and collagen deposition. SHR-T exhibited prompt and marked decrease in LV Ang II content (T1 vs T4 in WKY-T), normalized oxidative stress (T2), augmented antioxidant defense (T4) and reduced both collagen deposition and inflammatory profile (T8), without changing cardiomyocytes’ diameter and LV hypertrophy. These changes were accompanied by decreased plasma Ang II content (T2-T4) and reduced BP (T8). SHR-T and WKY-T showed parallel increases in LV and plasma Ang-(1–7) content. Our data indicate that early training-induced downregulation of LV ACE-AngII-AT1 receptor axis is a crucial mechanism to reduce oxidative/pro-inflammatory profile and improve antioxidant defense in SHR-T, showing in addition this effect precedes plasma RAS deactivation

Sequential changes on heart oxidative stress and antioxidant defense.

<p>Temporal changes of reactive oxygen species (A, illustrative photomicrographs; scale bars = 50 μm; B, quantification of dihydroethidium staining, DHE) and catalase expression (C) and activity (D) in the left ventricle of sedentary (S) and trained (T) SHR and WKY during the 8 weeks’ protocols. DHE staining was measured in 4 rats/group (approximately 12–15 visual fields/rat); catalase expression and activity were evaluated in 4 to 6 rats/group. Significance is P<0.05 * <i>vs</i> WKY; † <i>vs</i> week 0; # T₈ <i>vs</i> S₈.</p

Training-induced changes on NF-kB, pro- and anti-inflammatory cytokines in the heart.

<p>Temporal changes of NF-kB translocation to the nucleus (A, gel shift assay for the p65 NF-kB monomer; B, measurements of optical density), TNF alpha (C), interleukin-1β (Il1b, D) and interleukin-10 (Il10, E) mRNA expression in the left ventricle of sedentary (S) and trained (T) SHR and WKY during the 8 weeks’ protocols. NF-kB translocation was measured in 5 rats/group and genes’ expression in 4 to 6 rats/group. Significance is P<0.05 * <i>vs</i> WKY; † <i>vs</i> week 0; # T₈ <i>vs</i> S₈.</p

Sequential changes on treadmill performance in normotensive (WKY) and spontaneously hypertensive rats (SHR) submitted to sedentary (S) or training (T) protocols.

<p>Sequential changes on treadmill performance in normotensive (WKY) and spontaneously hypertensive rats (SHR) submitted to sedentary (S) or training (T) protocols.</p

Sequential changes on body weight (BW) and left ventricle (LV) weight in normotensive (WKY) and spontaneously hypertensive rats (SHR) submitted to sedentary (S) or training (T) protocols.

<p>Sequential changes on body weight (BW) and left ventricle (LV) weight in normotensive (WKY) and spontaneously hypertensive rats (SHR) submitted to sedentary (S) or training (T) protocols.</p

Sequential training-induced effects on cardiac remodeling.

<p>Time-related <b>c</b>hanges of left ventricle hypertrophy, as measured by LV/tibia length ratio (A), cardiomyocytes’ diameter at the end of protocols (B, illustrative photomicrographs, scale bars = 50μm; C, quantitative data), atrial natriuretic peptide (Nppa, D) and α-actin (Acta1, E) mRNA tissue expression in sedentary (S) and trained (T) SHR and WKY during the 8 weeks’ protocols. Cardiomyocytes’ diameter was measured in 3 to 4 rats/group (approximately 80 myocytes/rat) and gene expression in 4 to 6 rats/group. Significance is P<0.05 * <i>vs</i> WKY; † <i>vs</i> week 0; # T₈ <i>vs</i> S₈.</p

Training-induced changes on cardiac collagen expression.

<p>Changes of collagen content over time (A, illustrative photomicrographs, scale bars = 50μm; B quantitative data) and collagen I (C) and collagen III (D) mRNA expression in the left ventricle of sedentary (S) and trained (T) SHR and WKY during the 8 weeks’ protocols. Collagen content (picrossirius red) was measured in 3 to 4 rats/group (~20 visual fields/rat) and gene expression in 4 to 6 rats/group Significance is P<0.05 * <i>vs</i> WKY; † <i>vs</i> week 0; # T₈ <i>vs</i> S₈.</p