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

Abstract

Key points• Physical exercise is recommended as first line therapy for hypertensive patients. However, studies investigating long-term effects of high intensity exercise on the progression of hypertensive heart disease have revealed conflicting results.• We show that high intensity aerobic exercise accelerates hypertensive heart disease and improves fibrosis.• Surprisingly, high intensity aerobic exercise in the presence of an angiotensin converting enzyme inhibitor not only attenuated training induced mal-adaptation but exerts positive repair processes. These effects were independent of blood pressure effects.• The results of this study provide evidence that high physical activity in hypertensives must be considered as an important risk factor rather than a therapeutic intervention. AbstractIn 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 Abbreviations ACE, angiotensin converting enzyme; NCX, Na + -Ca 2+ exchanger; Nrf-1, nuclear respiratory factor-1; PGC-1α, peroxisome proliferator activated receptor γ coactivator 1α; RAS, renin-angiotensin system; SERCA, sarcoplasmatic reticulum Ca 2+ -ATPase; SHR, spontaneously hypertensive rat; TGF-β1, transforming growth factor-β1.

Cardiac Effects of Exercise Training in Hypertension

“…Some reports even suggest that exercise training can reduce the development of �brosis in established pathologic hypertrophy [61]. However, a very recent paper has shown that high levels of wheel running velocity in SHR rats can induce a pro�brotic phenotype and is positively correlated with LV mRNA of TGF-1, collagen III, and biglycan, whereas wheel running velocity was negatively correlated with SERCA2A to Na + -Ca 2+ exchanger ratio [62].…”

“…While extreme levels of acute and chronic exercise may be deleterious to the heart by increasing apoptosis, �brosis, and ischemic dysfunction [62,113,114], moderate levels of exercise seem protective from cardiac damage. ese animal studies support the American College of Sports Medicine recommendation for encouragement of exercise on most, if not all, days of the week, at moderate intensities, by accumulating 30 minutes or greater of endurance-style physical activity [7].…”

Mechanism and consequences of the shift in cardiac arginine metabolism following ischaemia and reperfusion in rats

“…Protein was extracted as described before (25). The lysis buffer contained (mmol/l): Tris-HCl (pH 7.5) 20, NaCl 150, EGTA 1, EDTA 2, Triton (1 % v/v), sodium pyrophosphate (2.5), β-glycerophosphate 1, Na 3 VO 4 1, leupeptin (1 µg/ml) (Cell Signalling Technology, Leiden, Netherland).…”

“…Tissue samples were prepared to analyse the steady-state mRNA levels of proteins of interest according to the previously described method (25). Briefly, total RNA was isolated from the left ventricles using peqGoldTriFast (peqlab, Biotechnology GmbH, Erlangen, Germany) according to the manufacturer's protocol.…”

“…Thereafter hearts were rapidly excised and the aorta was cannulated for retrograde perfusion with a 16-gauge needle connected to a Langendorff perfusion system. Left ventricular function was determined by insertion of a water filled balloon into the left ventricle as described before (25). Hearts were paced during measurements.…”