Cellular mechanisms of cardiomyopathy Harvey, Pamela A.; Leinwand, Leslie A.
The Journal of cell biology,
08/2011, Volume:
194, Issue:
3
Journal Article
Peer reviewed
Open access
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. Although 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 and in common animal models of CVD.
Antibiotic‐resistant infections are projected to cause over 10 million deaths annually by 2050. Despite this growing global crisis, there is waning interest in antimicrobial development due to ...declining financial incentives and regulatory barriers. There exists a critical need for identification of novel antimicrobial agents. Nearly 75% of US FDA‐approved antibiotics are derived from natural sources. Both plant oils and extracts have been recognized for their potent antimicrobial properties in Gram‐positive and –negative bacteria. However, few investigators have thoroughly explored the effects of individual active compounds that compose these oils. Melaleuca alternifolia (tea tree) oil has been shown to exert broad‐spectrum antimicrobial effects in several bacterial species. We hypothesized that these properties are attributable to monoterpenoid compounds that can diffuse through and disrupt cell membranes. Seven of the most abundant monoterpenoids in Melaleuca alternifolia (tea tree) oil ρ‐cymene, eucalyptol, (R)‐(+)‐limonene, linalool, terpinen‐4‐ol, α‐terpinene, and terpinolene were tested individually against SalmonellaTyphimurium, a Gram‐negative bacterium with up to 70% of strains exhibiting resistance to one or more antibiotic. The Mueller‐Hinton agar well diffusion test was used to determine antimicrobial activity through measurement of zones of inhibition. The minimal inhibitory concentration (MIC) and half‐maximal inhibitor concentration (IC50) of the subset of compounds exhibiting antimicrobial effects (linalool, terpinen‐4‐ol, α‐terpinene, and terpinolene) were also determined. MIC and IC50 values were 0.78% ‐ 6.25% and 1.5% ‐ 50% vol/vol, respectively. Each compound exerted its effects through bacteriostatic mechanisms as determined by time‐kill assays. These data highlight a continued role for natural products in the search for novel antimicrobials and importantly, identify the chemical components of Melaleuca alternifolia oil that confer its antimicrobials effects.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
It is now well established that global to local climate is impacted by volcanic forcing associated with major eruptions. Much attention has been given to the way in which climate is affected by such ...eruptions, particularly for the Northern Hemisphere, and to a considerably lesser extent for the Southern Hemisphere. Research knowledge gaps remain on such forcing impacts at finer sub‐regional spatial scales. To this end, we explore temperature responses across eight sub‐regions of Australia following three major volcanic eruptions (i.e., Krakatau, 1883; Santa Maria, 1902; Pinatubo, 1991) as simulated by CMIP5 models. We then compare such responses with station and reanalysis datasets. Model outputs indicate strongest temperature responses over more northerly regions than southerly regions of Australia, with weakest responses over Tasmania. Eastern regions of Australia seem to have strongest seasonal cooling during austral autumn, while that for northwestern coastal regions is during austral winter. In contrast, central regions of Australia cool most substantially during austral summer and/or winter, depending on the eruption. Despite such variability, initial temperature responses occur during the warmer austral months (September to February). Uncertainties exist in the reliability of CMIP5 data. For instance, temperature responses from the later Pinatubo eruption seem in stronger agreement with reanalysis data than earlier eruptions (Krakatau and Santa Maria), and while most seasonal temperature responses are stronger than those provided through reanalysis data, they are often weaker in austral spring.
Stronger temperature responses are indicated over more northerly regions than southerly regions of Australia, with weakest responses over Tasmania. Eastern regions of Australia seem to have strongest seasonal cooling during austral autumn, while that for northwestern coastal regions is during austral winter. In contrast, central regions of Australia cool most substantially during austral summer and/or winter, depending on the eruption. Despite such variability, initial temperature responses occur during the warmer austral months.
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Although volcanic forcing impacts on climate have gained much international attention during recent years, focus has largely been at hemispheric scale, and most particularly on the Northern ...Hemisphere (NH). Here we investigate the impact of major volcanic eruptions since 1883 on southern African climate, with a view to establishing potential sub‐regional differences across a variety of temporal scales. To this end, we use historical simulations from the Coupled Model Intercomparison Project, Phase 5 (CMIP5) to study near‐surface temperature responses to four major eruptions (Krakatau, 1883; Santa Maria, 1902; Agung, 1963; Pinatubo, 1991) over six sub‐regions of southern Africa. Results show significant cooling across all sub‐regions after each eruption. However, we detect considerable sub‐regional differences in the amplitude, timing and duration of responses. For instance, stronger temperature departures occur in northern rather than southern sub‐regions where diurnal and annual temperature ranges are normally greater. While significant responses occur within the first year after each eruption, there is a more delayed response in three of the sub‐regions (southwestern coast and central southern Africa) following the Santa Maria eruption. Strongest responses follow the Krakatau eruption in all sub‐regions, while the weakest response follows the Santa Maria eruption in western sub‐regions and the Agung eruption in eastern sub‐regions. Most regions experience the strongest temperature departures during austral autumn and winter (MAM and JJA), and weakest during spring (SON).
Considerable sub‐regional differences in amplitude, timing and duration of temperature responses are detected. The strongest negative departures occur in northern sub‐regions. A delayed response occurs over the southwestern coast and central southern Africa following the Santa Maria eruption. Strongest responses follow the Krakatau eruption in all sub‐regions, while the weakest responses follow the Santa Maria eruption in western sub‐regions and the Agung eruption in eastern sub‐regions. Most regions experience the strongest temperature departures during cooler austral seasons, and weakest during spring.
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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.
New classes of antibiotics are needed to fight bacterial infections, and repurposing existing drugs as antibiotics may enable rapid deployment of new treatments. Screens for antibacterials have been ...traditionally performed in standard laboratory media, but bacterial pathogens experience very different environmental conditions during infection, including nutrient limitation. To introduce the next generation of researchers to modern drug discovery methods, we developed a course-based undergraduate research experience (CURE) in which undergraduate students screened a library of FDA-approved drugs for their ability, in a nutrient-poor medium, to prevent the growth of the human Gram-negative bacterial pathogen Salmonella enterica serovar Typhimurium. The nine drugs identified all disrupt DNA metabolism in bacteria and eukaryotes. One of the hit compounds, capecitabine, is a well-tolerated oncology drug that is administered orally, a preferred treatment route. We demonstrated that capecitabine is more effective at inhibiting
Typhimurium growth in nutrient-limited than in standard rich microbiological broth, an explanation for why the antibiotic activity of this compound has not been previously recognized. Capecitabine is enzymatically converted to the active pyrimidine analogue, fluorouracil (5-FU), and Gram-positive bacteria, including Staphylococcus aureus, are significantly more sensitive to 5-FU than Gram-negative bacteria. We therefore tested capecitabine for efficacy in a murine model of S. aureus peritonitis. Oral capecitabine administration reduced the colonization of tissues and increased animal survival in a dose-responsive manner. Since capecitabine is inexpensive, orally available, and relatively safe, it may have utility for treatment of intractable Gram-positive bacterial infections.
As bacterial infections become increasingly insensitive to antibiotics, whether established, off-patent drugs could treat infections becomes an important question. At the same time, basic research has revealed that during infection, mammals starve pathogens for nutrients and, in response, bacteria dramatically alter their biology. Therefore, it may be fruitful to search for drugs that could be repurposed as antibiotics using bacteria grown with limited nutrients. This approach, executed with undergraduate student researchers, identified nine drugs known to interfere with the production and/or function of DNA. We further explored one of these drugs, capecitabine, a well-tolerated human oncology drug. Oral administration of capecitabine reduced infection with the human pathogen Staphylococcus aureus and increased survival in mice. These data suggest that capecitabine has potential as a therapy for patients with otherwise untreatable bacterial infections.
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.
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