Long-term MMP inhibition by doxycycline exerts divergent effect on ventricular extracellular matrix deposition and systolic performance in stroke-prone spontaneously hypertensive rats.

摘要

Pharmacologic inhibition of matrix metalloproteinases (MMP) by doxycycline is of therapeutic potential for a number of cardiovascular diseases characterized by excessive activation of MMP. So far, long-term administration of doxycycline in the treatment of hypertensive ventricular remodeling has not been systemically investigated. Seven-week-old stroke-prone spontaneously hypertensive rats (SHRSP) were fed with doxycycline (30 mgKg(-1) daily) for 26 weeks, when the mortality rate of the control group reached 50%. Stroke incidence was recognized by daily monitoring of stroke symptoms. Left ventricular (LV) performance was measured by in-vivo pressure-volume loop analysis and ex-vivo passive pressure-volume relationship at the time of sacrifice. Collagen deposition, gelatinases activity, protein abundance of gelatinases, and tissue inhibitor of matrix metalloproteinases (TIMP) -1, -2, and related mRNA levels in the heart were determined. MMP-9 expression was not detected in all groups. Excessive activation of MMP-2 in the heart could be partially suppressed by doxycycline. Left ventricular systolic function and ventricular size was partially ameliorated by doxycycline; however, elevated collagen deposition co-existed in the heart. Moreover, doxycycline could downregulate MMP-2 and TIMP-1 expression both at mRNA and protein levels, and TIMP-2 represented opposite expression pattern. These results demonstrate that long-term administration of doxycycline during the development of hypertension has no impact on stroke death, and could partially preserve LV systolic performance and restrain LV chamber dilation, but leads to increased LV extracellular matrix accumulation. Interrupted cardiac MMP-2/TIMP-2 balance by doxycycline may play a role in this process.