Treadmill exercise prevents reduction of bone mineral density after myocardial infarction in apolipoprotein E-deficient mice.

AIMS: Recent clinical studies demonstrated the association between myocardial infarction (MI) and osteoporotic fractures. We examined whether MI causes bone loss and the effects of exercise training on bone in mice after MI. METHODS: We created a MI model in 16-week-old male apolipoprotein E-deficient mice (n = 42), which were randomly assigned to exercise group (MI-Ex) and sedentary group (MI-Sed). We also performed sham operations in other mice (n = 10). Treadmill exercise training was performed from one week after operation to eight weeks. At eight weeks, the bone parameters of the femur were measured by quantitative computed tomography, followed by histological analysis (n = 10-17). RESULTS: Bone mineral density (BMD) of the femur was significantly decreased in the MI-Sed group as compared with the sham group (P < 0.001), whereas the BMD was significantly increased in the MI-Ex group as compared with the MI-Sed group (P < 0.05). In histological analysis, Rho-associated coiled-coil kinase 2 and tartrate-resistant acid phosphate positive (bone resorptive) area in distal femur were significantly increased in the MI-Sed group as compared with the sham group (P < 0.05), whereas those parameters were significantly decreased in the MI-Ex group as compared with the MI-Sed group (P < 0.05). In contrast, alkaline phosphatase (ALP)-positive (bone-forming) area was significantly decreased in the MI-Sed group as compared with the sham group (P < 0.05), whereas ALP-positive area was significantly increased in the MI-Ex group as compared with the MI-Sed group (P < 0.05). CONCLUSIONS: The present study demonstrates that MI reduces BMD and treadmill exercise training prevents the reduction of BMD in apolipoprotein E-deficient mice.

Combination therapy with atorvastatin and amlodipine suppresses angiotensin II-induced aortic aneurysm formation.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs. METHODS AND RESULTS: Experimental AAA was induced in Apolipoprotein E-deficient (ApoE(-/-)) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects. CONCLUSIONS: Rho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho-kinase inhibition may be involved.