Animals must balance their energy budget despite seasonal changes in both energy availability and physiological expenditures. Immunity, in addition to growth, thermoregulation, and cellular maintenance, requires substantial energy to maintain function, although few studies have directly tested the energetic cost of immunity. The present study assessed the metabolic costs of an antibody response. Adult and aged male C5BL/6J mice were implanted with either empty Silastic capsules or capsules filled with melatonin and injected with either saline or keyhole limpet hemocyanin (KLH). O2 consumption was monitored periodically throughout antibody production using indirect calorimetry. KLH-injected mice mounted significant immunoglobulin G (IgG) responses and consumed more O2 compared with animals injected with saline. Melatonin treatment increased O2 consumption in mice injected with saline but suppressed the increased metabolic rate associated with an immune response in KLH-injected animals. Melatonin had no effect on immune response to KLH. Adult and aged mice did not differ in antibody response or metabolic activity. Aged mice appear unable to maintain sufficient heat production despite comparable O2 production to adult mice. These results suggest that mounting an immune response requires significant energy and therefore requires using resources that could otherwise be allocated to other physiological processes. Energetic trade-offs are likely when energy demands are high (e.g., during winter, pregnancy, or lactation). Melatonin appears to play an adaptive role in coordinating reproductive, immunologic, and energetic processes.

Increased angiotensin II (Ang II), matrix metalloproteinase type II (MMP2), and sympathetic activity accompany age-associated arterial remodeling. To analyze this relationship, we infused a low subpressor dose of Ang II into young (8 months old) rats. This increased carotid arterial MMP2 transcription, translation, and activation, as well as transforming growth factor-␤1 activity and collagen deposition. A higher Ang II concentration, which increased arterial pressure to that of old (30 months old) untreated rats, produced carotid media thickening and intima infiltration by vascular smooth muscle cells (VSMCs). Ex vivo, Ang II increased MMP2 activity in carotid rings from young rats to that of untreated old rats. Ang II also increased the ability of early passage VSMCs from young rats to invade a synthetic basement membrane, similar to that of untreated VSMCs from old rats. The MMP inhibitor GM6001 and the AT 1 receptor antagonist Losartan inhibited these effects. The ␣-adrenoreceptor agonist phenylephrine increased arterial Ang II protein, causing MMP2 activation and intima and media thickening. Exposure of young VSMCs to phenylephrine in vitro increased Ang II protein and MMP2 activity to the levels of old VSMCs; Losartan abolished these effects. Thus, Ang II-induced effects on MMP2, transforming growth factor-␤1, collagen, and VSMCs are central to the arterial remodeling that accompanies advancing age. (Am J Pathol 2005,

Erythropoietin (EPO), well known for its role in stimulation of erythropoiesis, has recently been shown to have a dramatic neuroprotective effect in animal models of cerebral ischemia, mechanical trauma of the nervous system, and excitotoxins, mainly by reducing apoptosis. We studied the effect of single systemic administration of recombinant human EPO (rhEPO) on left ventricular (LV) size and function in rats during 8 weeks after the induction of a myocardial infarction (MI) by permanent ligation of the left descending coronary artery. We found that an i.p. injection of 3,000 units͞kg of rhEPO immediately after the coronary artery ligation resulted, 24 h later, in a 50% reduction of apoptosis in the myocardial area at risk. Eight weeks after the induction of MI, rats treated with rhEPO had an infarct size 15-25% of the size of that in untreated animals. The reduction in myocardial damage was accompanied by reductions in LV size and functional decline as measured by repeated echocardiography. Thus, a single dose of rhEPO administered around the time of acute, sustained coronary insufficiency merits consideration with respect to its therapeutic potential to limit the extent of resultant MI and contractile dysfunction. E rythropoietin (EPO), a cytokine produced by the adult kidney, is a well known hematopoietic factor. EPO receptors (EPO-Rs) are expressed in adult bone marrow and spleen and are activated by hypoxia (1). Whether EPO-Rs are present in nonhematopoietic tissues is less certain. The predominant opinion is that the expression of EPO-Rs in nonhematopoietic tissues is limited to the fetal stage of development (2). Although some studies failed to detect EPO-R transcripts in the brain, kidney, liver, or heart of adult mice (3), others have reported an intensive immunoreactivity for EPO-Rs in many medium and large neurons of adult rat brain (4). Moreover, a weak EPO-R immunoreactivity of human brain was amplified by hypoxia (5). Recently, EPO-Rs have also been identified in the adult retina of mice (6). Although EPO-Rs have not been identified in adult hearts, their presence during embryogenesis is critical for cardiac development (7).Recombinant human EPO (rhEPO) is widely used for the treatment of anemia occurring in the context of surgery, cancer, HIV, kidney failure, etc. (8). Recently, rhEPO has been shown to have a dramatic neuroprotective effect in animal models of cerebral ischemia and mechanical trauma of the nervous system, and in response to excitotoxins. A single intracerebroventricular injection and, more importantly, systemic administration of rhEPO have resulted in a 50-75% reduction in brain injury induced by the focal ischemia (4). A reduction of apoptosis is a mechanism involved in this neuroprotective effect of rhEPO (9, 10).We hypothesized that the protective effect of systemic rhEPO administration that resulted in improvement of brain cell survival after cerebral ischemia would also occur in the ischemic heart model. Specifically, we studied the effect of a single systemic administration...