High-Intensity Exercise Promotes Deleterious Cardiovascular Remodeling in a High-Cardiovascular-Risk Model: A Role for Oxidative Stress
<p>Impact of different loads of regular training on cardiovascular risk factors. (<b>A</b>) Weekly measurement (estimated marginal mean ± standard error of the mean {SEM}) of body weight. Analysis with linear mixed modeling with a repeated measures covariance structure, including week, group, and its interaction as predictors. The time point × group interaction was significant at the <span class="html-italic">p</span> < 0.001 level; within each week, significant post hoc pairwise comparisons between groups (LSD tests) are shown. N = 10 per group. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01 INT vs. Sed (<b>B</b>) Indexed body weight (BW) before euthanasia. Analysis with a linear trend analysis. * <span class="html-italic">p</span> < 0.05. (<b>C</b>) Results (estimated marginal mean ± SEM) of the intraperitoneal glucose tolerance test. Analysis with linear mixed modeling with a repeated measures covariance structure, including time point, group, and its interaction as predictors. The time point × group interaction was significant at the <span class="html-italic">p</span> < 0.001 level; within each time point, significant post hoc pairwise comparisons between groups (LSD tests) are shown. N = 10 per group. ** <span class="html-italic">p</span> < 0.01 SED vs MOD; + <span class="html-italic">p</span> < 0.05 SED vs INT. (<b>D</b>) Area under the curve (AUC, mean ± SD) of glucose blood concentrations during the glucose test. Analysis was performed with a one-way ANOVA which showed a significant omnibus test at the <span class="html-italic">p</span> < 0.05 level. Significant pairwise LSD tests are shown. * <span class="html-italic">p</span> < 0.05. (<b>E</b>) Serum insulin concentration (mean ± SD) before and 30 min after glucose administration. Analysis with linear mixed modeling with a repeated measures covariance structure, including time point (i.e., baseline and 30 min) and group and its interaction as predictors. The interaction time point × group was significant at the <span class="html-italic">p</span> < 0.05 level; within each group, significant post hoc pairwise comparisons between time points (baseline vs. 30-min, LSD tests) are shown. ** <span class="html-italic">p</span> < 0.01. (<b>F</b>) Triglyceride plasma concentration (mean ± SD) in all groups. Analysis was performed with a one-way ANOVA. SED, MOD, and INT (obese sedentary, moderately and intensively trained rats, respectively).</p> "> Figure 2
<p>Echocardiographic changes produced by exercise. (<b>A</b>) Ascending aortic diameter (mean ± SD). Analysis with a linear trend analysis. (<b>B</b>) Representative M-mode images of a parasternal long-axis view. The segmented blue line identifies the interventricular septum (IVS) and the green arrow identifies the left ventricular diastolic diameters (LVDd). (<b>C</b>–<b>H</b>) The mean ± SD is shown for indexed IVS (iIVS) (<b>C</b>), indexed LVDd (iLVDd) (<b>D</b>), indexed left ventricle posterior wall (iLVPW) (<b>E</b>), left ventricle ejection fraction (<b>F</b>) and fractional shortening (<b>G</b>), and transmitral E/A ratio (<b>H</b>). All analyses were performed with a one-way ANOVA which showed a significant omnibus test at the <span class="html-italic">p</span> < 0.05 level for iVS, iLVDd, ejection fraction, and fractional shortening. Post hoc pairwise comparisons were performed with the LSD tests. * <span class="html-italic">p</span> < 0.05. SED, MOD, and INT (obese sedentary, moderately and intensively trained rats, respectively).</p> "> Figure 3
<p>Aortic collagen deposition and turnover. (<b>A</b>) Percentage of collagen deposit in the tunica media from picrosirius red-stained thoracic aorta (mean ± SD). (<b>B</b>–<b>D</b>) Aortic mRNA expression (mean ± SD) of alpha-1 procollagen types 1 (<b>B</b>) and 3 (<b>C</b>), and matrix metalloproteinase-2. Analyses were performed with one-way ANOVA which showed a significant omnibus test at the <span class="html-italic">p</span> < 0.0001 level for gene expression parameters. Post hoc pairwise comparisons (<span class="html-italic">t</span>-tests) were FDR-adjusted. * <span class="html-italic">p</span> < 0.05; **** <span class="html-italic">p</span> < 0.0001. SED, MOD, and INT (obese sedentary, moderately, and intensively trained rats, respectively), CTL (young lean rats).</p> "> Figure 4
<p>Relaxation response in vascular reactivity experiments in descending thoracic aorta. Dose-response relaxation curves induced by carbachol (CCH) alone (<b>A</b>) and in the presence of nitric oxide inhibitor LNMMA (<b>B</b>), sodium nitroprusside (SNP) in the presence of L-NMMA (<b>C</b>), and carbachol in the presence of the free radical scavenger TEMPOL (<b>D</b>). Shaded areas of all curves represent 95% CI. The estimated logEC50 (mean ± SEM) for each group and curve is shown in the inset. Analyses were performed with a one-way ANOVA per each individual graph, comparing fitted logEC50 in three parameter equations. Significant post hoc pairwise FDR-adjusted comparisons between groups are shown, * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, and *** <span class="html-italic">p</span> < 0.001. SED, MOD, and INT (obese sedentary, moderately, and intensively trained rats, respectively), CTL (young lean rats). For all experiments: n = 9 (SED), n = 10 (MOD), n = 10 (INT, except for panel 4C in which n = 9), and n = 8 (CTL).</p> "> Figure 5
<p>Contractile response in vascular reactivity experiments in descending thoracic aorta. Dose-response contraction curves induced by phenylephrine (PHE) alone (<b>A</b>) and in the presence of the nitric oxide inhibitor L-NMMA (<b>B</b>) or the free radical scavenger TEMPOL (<b>C</b>). Shaded areas of all curves represent 95% CI. Estimated LogEC50 (mean ± SEM) for each group and curve is shown. Analyses were performed with a one-way ANOVA per each individual graph, comparing fitted logEC50 in three parameter equations. Significant post hoc pairwise FDR-adjusted comparisons between groups are shown, * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001, and **** <span class="html-italic">p</span> < 0.0001. SED, MOD, and INT (obese sedentary, moderately, and intensively trained rats, respectively), CTL (young lean rats). For all experiments: n = 6 (SED, except for panel (<b>C</b>) in which n = 5), n = 11 (MOD), n = 9 (INT), and n = 8 (CTL).</p> "> Figure 6
<p>Oxidative stress imbalance in aortic and perivascular adipose tissue. (<b>A</b>) Aortic mRNA expression (mean ± SD) of pro-oxidant markers. (<b>B</b>) Aortic mRNA expression (mean ± SD) of antioxidant markers. (<b>C</b>) Representative images of Nrf2 nuclei translocation in the aortic thoracic wall (upper panel; nuclei stained in blue {DAPI}, Nrf2 in red, when translocated to the nuclei appears pink/purple), and percentage (mean ± SD) of positive nuclei in the tunica media (lower panel). (<b>D</b>) Perivascular adipose tissue (PVAT) mRNA expression of pro-oxidant markers (mean ± SD). (<b>E</b>) PVAT mRNA expression of antioxidant markers (mean ± SD). Analyses were performed at the gene level with a one-way ANOVA, significant post hoc pairwise comparisons between groups (FDR adjustment for (<b>A</b>,<b>B</b>), LSD tests for (<b>D</b>,<b>E</b>) are shown, * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001. SED, MOD, and INT (obese sedentary, moderately and intensively trained rats, respectively), CTL (young lean rats).</p> "> Figure 7
<p>Left ventricular myocardial histological assessment. (<b>A</b>) Representative triple immunofluorescence images of myocardial triple immunofluorescence (wheat germ agglutinin in red for extracellular matrix, vimentin in blue for fibroblasts, and isolectin-GS IB4 in green for capillaries). Results (mean ± SD) for the left ventricular (LV) myocyte cross-sectional area (CSA) in the LV free wall and the interventricular septum (IVS) ((<b>B</b>,<b>C</b>), respectively), extracellular matrix content in the LV free wall and the IVS (<b>D</b>,<b>E</b>), vimentin-positive area in the LV free wall and the IVS (<b>F</b>,<b>G</b>), and capillary density in the LV free wall and the IVS (<b>H</b>,<b>I</b>). Analyses were performed with a one-way ANOVA, and significant post hoc pairwise FDR-adjusted comparisons between groups are shown, * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, and *** <span class="html-italic">p</span> < 0.001. SED, MOD, and INT (obese sedentary, moderately, and intensively trained rats, respectively), CTL (young lean rats).</p> "> Figure 8
<p>Expression of genes involved in cardiac remodeling in all groups. Interventricular septum mRNA expression (mean ± SD) of the α- and β-myosin heavy chain isoforms (Mhc) (<b>A</b>) and their ratio (<b>B</b>), titin isoforms N2b and N2ba (<b>C</b>), and their ratio (<b>D</b>), Bnp (<b>E</b>), Igfr1 (<b>F</b>), and Mef2d (<b>G</b>). Analyses were performed at the gene level with a one-way ANOVA, significant post hoc pairwise FDR-adjusted comparisons between groups are shown, * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001, and **** <span class="html-italic">p</span> < 0.0001. SED, MOD, and INT (obese sedentary, moderately, and intensively trained rats, respectively), CTL (young lean rats).</p> "> Figure 9
<p>Myocardial collagen deposition. (<b>A</b>) Representative images of picrosirius red-stained samples (<b>left panel</b>) and quantification of myocardial fibrosis (mean ± SD, <b>right panel</b>) in the left ventricle free wall (LVFW), interventricular septum (IVS), and right ventricle free wall (RVFW). Analysis was performed with a linear mixed effects modeling, including group, chamber, and their interaction as predictors; both group and cardiac chamber were significant at the <span class="html-italic">p</span> < 0.001 level, and significant post hoc pairwise comparisons within the group main factor are shown (<span class="html-italic">p</span>-values are FDR-adjusted). (<b>B</b>–<b>E</b>) mRNA expression (mean ± SD) of alpha-1 procollagen types 1 (<b>B</b>) and 3 (<b>C</b>), matrix metalloproteinase-2 (<b>D</b>), and tissular metalloproteinase inhibitor 1 (<b>E</b>). Analyses were performed at the gene level with a one-way ANOVA, and significant post hoc pairwise FDR-adjusted comparisons between groups are shown. *** <span class="html-italic">p</span> < 0.001, and **** <span class="html-italic">p</span> < 0.0001. SED, MOD, and INT (obese sedentary, moderately, and intensively trained rats, respectively), CTL (young lean rats).</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animal Model and Exercise Protocol
2.2. Urine and Plasma Collection and Analysis
2.3. Glucose Tolerance Test and Insulin Determination
2.4. Echocardiogram
2.5. Euthanasia
2.6. Vascular Reactivity
2.7. Heart and Vascular Histology Assessment
2.7.1. Picrosirius Red
2.7.2. Aortic NRF2 Immunofluorescence
2.7.3. Heart Triple Immunofluorescence
2.8. Expression of mRNA in Cardiac Tissue, Aorta, and PVAT
2.9. Statistical Analysis
3. Results
3.1. Exercise Improves Glycosidic Metabolic Profile in Zucker Rats
3.2. Unilateral Nephrectomy Elicits a Mild Impairment in Renal Function
3.3. Exercise Induces Structural Aortic Remodeling
3.4. Moderate Exercise Enhances Endothelial Function
3.5. Oxidative Stress Modulates Endothelial Function in Intensively Trained Rats
3.6. Cardiac Phenotype Diverges Depending on Exercise Intensity in Rats at High CV Risk
3.7. Intensive Exercise Tends to Induce an Inflammatory Profile
4. Discussion
4.1. An Animal Model to Fill the Gap of Very Intense Exercise in Very High-Risk Patients
4.2. Improved Risk Profile in Heavily Trained Rats Is Not Paralleled by Vascular Prevention
4.3. Moderate Intensity Exercise Yields Larger Benefits in Preventing Obesity-Induced Cardiac Remodeling
4.4. Clinical Implications
4.5. Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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LogEC50 | Emax | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
SED | MOD | INT | CTL | ANOVA (Omnibus p) | SED | MOD | INT | CTL | ANOVA (Omnibus p) | |
CCH | −6.33 ± 0.10 ### | −7.04 ± 0.08 *** | −6.49 ± 0.07 *** | −6.51 ± 0.06 | <0.0001 | −89.54 ± 4.43 | −101.98 ± 3.36 | −95.67 ± 3.49 | −97.48 ± 2.99 | 0.13 |
CCH + LNMMA | −5.40 ± 0.24 | −5.86 ± 0.14 | −5.86 ± 0.14 | −5.48 ± 0.12 | 0.11 | −44.91 ± 7.57 | −51.43 ± 4.15 | −46.47 ± 3.74 | −46.22 ± 3.99 | 0.33 |
SNP + LNMMA | −7.97 ± 0.06 *,# | −7.76 ± 0.04 | −7.87 ± 0.05 | −7.76 ± 0.06 | 0.02 | −111.54 ± 2.27 * | −103.62 ± 1.46 * | −102.51 ± 1.81 * | −130.77 ± 2.94 | <0.0001 |
CCH + TEMPOL | −6.25 ± 0.13 *,###,& | −6.87 ± 0.08 | −6.79 ± 0.06 & | −6.64 ± 0.07 | 0.0003 | −84.83 ± 5.82 | −95.03 ± 3.21 | −86.48 ± 2.53 | −95.89 ± 3.06 | 0.10 |
PHE | −6.27 ± 0.11 **,# | −6.02 ± 0.07 *** | −6.17 ± 0.13 *** | −6.98 ± 0.08 | <0.0001 | 120.90 ± 7.01 | 118.39 ± 4.77 | 113.65 ± 7.93 | 103.39 ± 3.59 | 0.26 |
PHE + LNMMA | −6.96 ± 0.07 ** | −6.98 ± 0.04 *** | −7.01 ± 0.09 ** | −7.42 ± 0.07 | 0.0005 | 197.92 ± 6.31 | 205.10 ± 3.92 | 182.37 ± 6.88 *,# | 206.53 ± 5.60 | 0.01 |
PHE + TEMPOL | −6.04 ± 0.09 *** | −6.02 ± 0.08 *** | −6.06 ± 0.11 *** | −6.85 ± 0.05 | <0.0001 | 103.24 ± 5.16 | 122.47 ± 5.28 | 124.63 ± 7.51 | 122.65 ± 2.96 | 0.14 |
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Meza-Ramos, A.; Alcarraz, A.; Lazo-Rodriguez, M.; Sangüesa, G.; Banon-Maneus, E.; Rovira, J.; Ramirez-Bajo, M.J.; Sitges, M.; Mont, L.; Ventura-Aguiar, P.; et al. High-Intensity Exercise Promotes Deleterious Cardiovascular Remodeling in a High-Cardiovascular-Risk Model: A Role for Oxidative Stress. Antioxidants 2023, 12, 1462. https://doi.org/10.3390/antiox12071462
Meza-Ramos A, Alcarraz A, Lazo-Rodriguez M, Sangüesa G, Banon-Maneus E, Rovira J, Ramirez-Bajo MJ, Sitges M, Mont L, Ventura-Aguiar P, et al. High-Intensity Exercise Promotes Deleterious Cardiovascular Remodeling in a High-Cardiovascular-Risk Model: A Role for Oxidative Stress. Antioxidants. 2023; 12(7):1462. https://doi.org/10.3390/antiox12071462
Chicago/Turabian StyleMeza-Ramos, Aline, Anna Alcarraz, Marta Lazo-Rodriguez, Gemma Sangüesa, Elisenda Banon-Maneus, Jordi Rovira, Maria Jose Ramirez-Bajo, Marta Sitges, Lluís Mont, Pedro Ventura-Aguiar, and et al. 2023. "High-Intensity Exercise Promotes Deleterious Cardiovascular Remodeling in a High-Cardiovascular-Risk Model: A Role for Oxidative Stress" Antioxidants 12, no. 7: 1462. https://doi.org/10.3390/antiox12071462