Cardioprotection by systemic dosing of thymosin beta four following ischemic myocardial injury

Thymosin beta 4 (Tβ4) was previously shown to reduce infarct size and improve contractile performance in chronic myocardial ischemic injury via two phases of action: an acute phase, just after injury, when Tβ4 preserves ischemic myocardium via antiapoptotic or anti-inflammatory mechanisms; and a chronic phase, when Tβ4 activates the growth of vascular or cardiac progenitor cells. In order to differentiate between the effects of Tβ4 during the acute and during the chronic phases, and also in order to obtain detailed hemodynamic and biomarker data on the effects of Tβ4 treatment suitable for use in clinical studies, we tested Tβ4 in a rat model of chronic myocardial ischemia using two dosing regimens: short term dosing (Tβ4 administered only during the first 3 days following injury), and long term dosing (Tβ4 administered during the first 3 days following injury and also every third day until the end of the study). Tβ4 administered throughout the study reduced infarct size and resulted in significant improvements in hemodynamic performance; however, chamber volumes and ejection fractions were not significantly improved. Tβ4 administered only during the first 3 days following injury tended to reduce infarct size, chamber volumes and improve hemodynamic performance. Plasma biomarkers of myocyte injury were significantly reduced by Tβ4 treatment during the acute injury period, and plasma ANP levels were significantly reduced in both dosing groups. Surprisingly, neither acute nor chronic Tβ4 treatment significantly increased blood vessel density in peri-infarct regions. These results suggest the following: repeated dosing may be required to achieve clinically measureable improvements in cardiac function post-myocardial infarction (MI); improvement in cardiac function may be observed in the absence of a high degree of angiogenesis; and that plasma biomarkers of cardiac function and myocardial injury are sensitive pharmacodynamic biomarkers of the effects of Tβ4

Selective estrogen receptor modulation influences atherosclerotic plaque composition in a rabbit menopause model

Osteoporosis trials suggest raloxifene decreased cardiovascular events in women with pre-existing atherosclerosis. We assessed the hypothesis that selective estrogen receptor modulation induces plaque stability in “menopausal” animals. Atherosclerosis was induced in 42 ovariectomized New Zealand white rabbits by cholesterol feeding and mechanical injury. Animals were imaged by magnetic resonance imaging (MRI) for baseline atherosclerosis, and randomized to control (OVX (ovariectomized control group), n = 12), raloxifene 35–60 mg/kg/day by diet admixture (RLX (raloxifene therapy group), n = 24), or immediate sacrifice ( n = 6) for immunohistopathologic correlation of MRI. Six months later, rabbits underwent repeat MRI then sacrifice for micro-computed tomography (μCT) and molecular analysis. Unlike OVX, RLX reduced atheroma volume. Analysis for lesion inflammation revealed reductions in COX-2 (cyclooxygenase-2), MMP-1 (matrix metalloproteinase-1), MCP-1 (monocyte chemoattractant protein-1) expression and macrophage infiltration in RLX versus OVX with concomitant upregulation of estrogen receptor α (ERα). μCT showed similar total vascular calcification between groups, but calcifications in RLX were less nodular with better radial organization (mean calcific arc angle 63 ± 7° versus 33 ± 6° in OVX), the predicted result of a 53% increase in BMP-2 (bone-morphogenetic protein-2). Raloxifene treatment results in reduced lesion volume, enhanced mechanical stability of vascular calcification, and less inflamed lesions characterized by less macrophage infiltration and reduced COX-2, MMP-1 and MCP-1 expression