The heart exhibits remarkable adaptive responses to a wide array of genetic and extrinsic factors to maintain contractile function. When compensatory responses are not sustainable, cardiac dysfunction occurs, leading to cardiomyopathy. The many forms of cardiomyopathy exhibit a set of overlapping phenotypes reflecting the limited range of compensatory responses that the heart can use. These include cardiac hypertrophy, induction of genes normally expressed during development, fibrotic deposits that replace necrotic and apoptotic cardiomyocytes, and metabolic disturbances. The compensatory responses are mediated by signaling pathways that initially serve to maintain normal contractility; however, persistent activation of these pathways leads to cardiac dysfunction. Current research focuses on ways to target these specific pathways therapeutically.
Nearly one-third of deaths in the United States are caused by cardiovascular disease (CVD) each year. In the past, CVD was thought to mainly affect men leading to the exclusion of women and female animals from clinical studies and preclinical research. In light of sexual dimorphisms in CVD, a need exists to examine baseline cardiac differences in humans and the animals used to model CVD. In humans, sex differences are apparent at every level of cardiovascular physiology from action potential duration and mitochondrial energetics to cardiac myocyte and whole heart contractile function. Biological sex is an important modifier of the development of CVD with younger women generally being protected, but this cardioprotection is lost later in life, suggesting a role for estrogen. While endogenous estrogen is most likely a mediator of the observed functional differences in both health and disease, the signaling mechanisms involved are complex and are not yet fully understood. To investigate how sex modulates CVD development, animal models are essential tools and should be useful in the development of therapeutics. This review will focus on describing the cardiovascular sexual dimorphisms that exist both physiologically as well as in common animal models of CVD.
Dorsal root injury results in substantial and often irreversible loss of sensory functions as a result of the limited regenerative capacity of sensory axons and the inhibitory barriers that prevent both axonal entry into and regeneration in the spinal cord. Here, we describe previously unknown effects of the growth factor artemin after crush injury of the dorsal spinal nerve roots in rats. Artemin not only promoted re-entry of multiple classes of sensory fibers into the spinal cord and re-establishment of synaptic function and simple behavior, but it also, surprisingly, promoted the recovery of complex behavior. These effects occurred after a 2-week schedule of intermittent, systemic administration of artemin and persisted for at least 6 months following treatment, suggesting a substantial translational advantage. Systemic artemin administration produced essentially complete and persistent restoration of nociceptive and sensorimotor functions, and could represent a promising therapy that may effectively promote sensory neuronal regeneration and functional recovery after injury.Traumatic injury to the spinal dorsal roots often results in permanent sensory deficits 1,2 . Injured peripheral axons fail to enter the spinal cord at the dorsal root entry zone (DREZ) because of inhibitory barriers and an apparently limited regenerative capacity 2-6 . Oligodendrocytes, astrocytes, microglia and macrophages of the CNS produce growth inhibitory proteins, including Nogo, myelin-associated glycoprotein, and chondroitin sulfate proteoglycans 3,4,7,8 , that can alter the cytoarchitecture of regenerating peripheral axons and can cause growth cone collapse and cessation of growth 3,7,9 . Strategies aimed at altering the hostile central environment to permit axonal regrowth have shown some success. Increasing the levels of neurotrophic factors (for example, neurotrophin-3, nerve growth factor or glial cell line-derived neurotrophic factor, GDNF) by endogenous or exogenous means results in penetration of the DREZ by peripheral axons regenerating locally into the spinal cord 3,10,11 and limited restoration of nociceptive and sensorimotor functions 11 . To date, however, the extent of restoration of sensory functions by growth factors has been incomplete, and growth factors have not promoted recovery of more complex behaviors (for example, touch-evoked
A major impediment for regeneration of axons within the CNS is the presence of multiple inhibitory factors associated with myelin. Three of these factors bind to the Nogo receptor, NgR, which is expressed on axons. Administration of exogenous blockers of NgR or NgR ligands promotes the regeneration of descending axonal projections after spinal cord hemisection. A more detailed analysis of CNS regeneration can be made by examining the growth of specific classes of sensory axons into the spinal cord after dorsal root crush injury. In this study, we assessed whether administration of a soluble peptide fragment of the NgR (sNgR) that binds to and blocks all three NgR ligands can promote regeneration after brachial dorsal root crush in adult rats. Intraventricular infusion of sNgR for 1 month results in extensive regrowth of myelinated sensory axons into the white and gray matter of the dorsal spinal cord, but unmyelinated sensory afferents do not regenerate. In concert with the anatomical growth of sensory axons into the cord, there is a gradual restoration of synaptic function in the denervated region, as revealed by extracellular microelectrode recordings from the spinal gray matter in response to stimulation of peripheral nerves. These positive synaptic responses are correlated with substantial improvements in use of the forelimb, as assessed by paw preference, paw withdrawal to tactile stimuli and the ability to grasp. These results suggest that sNgR may be a potential therapy for restoring sensory function after injuries to sensory roots.
Obesity and elevated serum lipids are associated with a threefold increase in the risk of developing atherosclerosis, a condition that underlies stroke, myocardial infarction, and sudden cardiac death. Strategies that aim to reduce serum cholesterol through modulation of liver enzymes have been successful in decreasing the risk of developing atherosclerosis and reducing mortality. Statins, which inhibit cholesterol biosynthesis in the liver, are considered among the most successful compounds developed for the treatment of cardiovascular disease. However, recent debate surrounding their effectiveness and safety prompts consideration of alternative cholesterol-lowering therapies, including increasing cholesterol catabolism through bile acid (BA) synthesis. Targeting the enzymes that convert cholesterol to BAs represents a promising alternative to other cholesterol-lowering approaches that treat atherosclerosis as well as fatty liver diseases and diabetes mellitus. Compounds that modify the activity of these pathways have been developed; however, there remains a lack of consideration of biological sex. This is necessary in light of strong evidence for sexual dimorphisms not only in the incidence and progression of the diseases they influence but also in the expression and activity of the proteins affected and in the manner in which men and women respond to drugs that modify lipid handling in the liver. A thorough understanding of the enzymes involved in cholesterol catabolism and modulation by biological sex is necessary to maximize their therapeutic potential.
Artemin, a member of the glial-derived neurotrophic factor family, promotes robust regeneration of sensory axons after dorsal root crush. We report here that several classes of sensory axons regenerate to topographically appropriate regions of the dorsal horn with artemin treatment. Projections of regenerated muscle and cutaneous myelinated sensory afferents are restricted to the correct spinal segments and to appropriate regions within spinal gray matter. Regenerated unmyelinated axons expressing calcitonin gene-related peptide project only to superficial laminae of the dorsal horn, where uninjured nociceptive afferents project normally. In contrast, intraventricular infusion of a soluble form of the Nogo receptor that blocks the action of several myelin-associated inhibitory proteins promotes relatively unrestricted regeneration of sensory axons throughout the dorsal white and gray matter of the spinal cord. These results demonstrate that cues capable of guiding regenerating axons to appropriate spinal targets persist in the adult mammalian cord, but only some methods of stimulating regeneration allow the use of these cues by growing axons.artemin | central nervous system regeneration | dorsal root | soluble Nogo receptor peptide | specificity G rowth of damaged axons in the adult spinal cord is inhibited by the presence of myelin-associated proteins, up-regulation of proteoglycan expression, and the absence of appropriate growth factors. Several agents that can partially overcome this inhibition permit some regeneration of spinal axons in contusion or transaction models of spinal cord injury (SCI) (1-4); however, the limited regeneration and difficulty in labeling specific subclasses of axons with known projection patterns within the spinal cord have impeded progress in determining whether these regenerated projections are specific.The regeneration of sensory axons into the spinal cord after dorsal root (DR) crush provides a useful preparation for assessing the precision with which regenerating axons project back to appropriate target areas within the central nervous system (CNS). Regrowth of damaged sensory axons within the spinal cord can be visualized by injecting neurotracers into peripheral nerves. Identification of individual classes of axons can be achieved by making injections close to target tissues where nerve branches contain single classes of sensory afferents. Because only the DRs are damaged, the architecture of the spinal cord is left intact, allowing clear identification of the central projections of regenerated axons.Without treatment, sensory axons regenerate only to the DR entry zone (DREZ), where they encounter inhibitory barriers within the CNS (5, 6). Application of two agents-a soluble Nogo receptor peptide (sNgR), which binds to Nogo receptor ligands and abrogates their inhibitory effect (7), and artemin (ART), a member of the glial-derived neurotrophic factor familypromote robust regeneration of sensory axons after DR crush (8, 9). The specificity of projections of specific classes of...
The incidence of cardiac hypertrophy, an established risk factor for heart failure, is generally lower in women compared with men, but this advantage is lost after menopause. Although it is widely believed that estrogens are cardioprotective, there are contradictory reports, including increased cardiac events in postmenopausal women receiving estrogens and enhanced cardiac protection from ischemic injury in female mice without estrogens. We exposed aromatase knockout (ArKO) mice, which produce no estrogens, to both pathologic and physiologic stimuli. This model allows an investigation into the effects of a complete, chronic lack of estrogens in male and female hearts. At baseline, female ArKO mice had normal-sized hearts but decreased cardiac function and paradoxically increased phosphorylation of many progrowth kinases. When challenged with the pathological stimulus, isoproterenol, ArKO females developed 2-fold more hypertrophy than wild-type females. In contrast, exercise-induced physiological hypertrophy was unaffected by the absence of estrogens in either sex, although running performance was blunted in ArKO females. Thus, loss of estrogen signaling in females, but not males, impairs cardiac function and sensitizes the heart to pathological insults through up-regulation of multiple hypertrophic pathways. These findings provide insight into the apparent loss of cardioprotection after menopause and suggest that caution is warranted in the long-term use of aromatase inhibitors in the setting of breast cancer prevention.
Engagement in scientific research during undergraduate education improves conceptual understanding and retention in science. A laboratory-intensive course was created to offer the opportunity for students to participate in all aspects of research in collaboration with a sponsoring laboratory, providing students with an authentic research experience.
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