Adverse cardiac remodelling in spontaneously hypertensive rats: acceleration by high aerobic exercise intensity

Abstract

In the present study it was hypothesized that voluntary aerobic exercise favours a pro-fibrotic phenotype and promotes adverse remodelling in hearts from spontaneously hypertensive rats (SHRs) in an angiotensin II-dependent manner. To test this, female SHRs at the age of 1 year were started to perform free running wheel exercise. Captopril was used to inhibit the renin-angiotensin system (RAS). Normotensive rats and SHRs kept in regular cages were used as sedentary controls. Training intensity, expressed as mean running velocity, was positively correlated with the left ventricular mRNA expression of TGF-β(1), collagen-III and biglycan but negatively correlated with the ratio of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA)2a to Na(+)-Ca(2+) exchanger (NCX). A pro-fibrotic phenotype was verified by Picrosirius red staining. Sixty-seven per cent of SHRs performing free running wheel exercise died either spontaneously or had to be killed during a 6 month follow-up. In the presence of captopril, aerobic exercise did not show a similar positive correlation between training intensity and the expression of fibrotic markers. Moreover, in SHRs receiving captopril and performing free running wheel exercise, a training intensity-dependent reverse remodelling of the SERCA2a-to-NCX ratio was observed. None of these rats died spontaneously or had to be killed. In captopril-treated SHRs performing exercise, expression of mRNA for decorin, a natural inhibitor of TGF-β(1), was up-regulated. Despite these differences between SHR-training groups with and without captopril, positive training effects (lower resting heart rate and no progression of hypertension) were found in both groups. In conclusion, high aerobic exercise induces an angiotensin II-dependent adverse remodelling in chronic pressure overloaded hearts. However, high physical activity can potentially induce reverse remodelling in the presence of RAS inhibition.

Figure 1. Induction of PGC-1α and Nrf-1 by exercise in the left ventricle of SHRs

Data points from all rats are normalized to the mean expression of normotensive rats (Nx).

Figure 2. Correlation between training intensity and left ventricular TGF-β₁ expression in SHR-train and SHR-train + Capto

Expression is normalized to the mean expression of normotensive rats (Nx).

Figure 3. Correlation between training intensity and left ventricular collagen-III (Coll III) expression in SHR-train and SHR-train + Capto

Expression is normalized to the mean expression of normotensive rats (Nx).

Figure 4. Left ventricular collagen expression

Tissue slices were stained for total collagen (Pircosirius red; top; scale bar 100 μm). Mean staining intensities ± SD are given as bar graphs. *Significant difference from SHRs; #significant difference from SHR-train.

Figure 5. Correlation between training intensity and left ventricular biglycan expression in SHR-train and SHR-train + Capto

Expression is normalized to the mean expression of normotensive rats (Nx).

Figure 6. Correlation between training intensity and left ventricular decorin expression in SHR-train and SHR-train + Capto

Expression is normalized to the mean expression of normotensive rats (Nx).

Figure 7. Correlation between training intensity and left ventricular SERCA2a-to-NCX ratio in SHR-train and SHR-train + Capto

Expression is normalized to the mean expression of normotensive rats (Nx).

Figure 8. Left ventricular protein expression of sodium–calcium exchanger (NCX) and SERCA2a

A, original blots; B, mean data ± SD. *Significant difference from SHRs.

Figure 9. Left ventricular function of rat hearts from SHR, SHR-train, and SHR-train + Capto

Left ventricular developed pressure (LVDP) and the first derivative (+dp/dt) are given in A and B, respectively.