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Gregory J Wilson - One of the best experts on this subject based on the ideXlab platform.
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studying ischemic preconditioning in Isolated Cardiomyocyte models
Cardiovascular Research, 2006Co-Authors: Roberto J Diaz, Gregory J WilsonAbstract:Isolated Cardiomyocytes, obtained by enzymatic digestion of whole hearts, have multiple advantages, most related to their accessibility to microscopic visualization, beyond the obvious elimination of other cell types that exist in the heart. Conversely, they cannot reproduce the mechanical disruption of reperfusion hypercontracture or the vascular phenomena of leukocyte plugging and compression from interstitial edema and contracture that can lead to the no-reflow phenomenon. Nevertheless, ischemic preconditioning has been consistently demonstrated to be a potent protective mechanism in freshly Isolated and cultured Cardiomyocytes across multiple species, indicating that much of the innate protection of ischemic preconditioning resides in Cardiomyocytes. Centrifuging freshly Isolated Cardiomyocytes into a pellet with only a thin layer of supernatant covered by oil has proven to be an excellent model of simulated ischemia. In culture, Cardiomyocytes may be exposed to severe hypoxia only or to various protocols for simulated ischemia in which an acid/lactate-rich, hyperkalemic extracellular environment with substrate deprivation (lacking glucose) is typically added. Reperfusion is simulated by well-oxygenated media of normal ionic composition. Cardiomyocyte injury has been usually evaluated by cell membrane permeability to dyes, often under hypo-osmotic conditions (osmotic fragility) or enzyme release. A survey of the use of Cardiomyocyte models to study preconditioning is presented with the emphasis on examples of the innovative measurements, increasingly involving molecular techniques, that point to an increasing future role for these models in preconditioning research and, more generally, in the mechanistic study of myocardial ischemia/reperfusion.
Pamela A Lucchesi - One of the best experts on this subject based on the ideXlab platform.
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in vivo and in vitro cardiac responses to beta adrenergic stimulation in volume overload heart failure
Journal of Molecular and Cellular Cardiology, 2013Co-Authors: Kirk R Hutchinson, Anuradha Guggilam, Aaron T West, Amy P Kelly, Maarten L Galantowicz, Amy J Davidoff, Sakthivel Sadayappan, Pamela A LucchesiAbstract:Abstract Hearts in volume overload (VO) undergo progressive ventricular hypertrophy resulting in chronic heart failure that is unresponsive to β-adrenergic agonists. This study compared left ventricular (LV) and Isolated Cardiomyocyte contractility and β-adrenergic responsiveness in rats with end-stage VO heart failure (HF). Adult male Sprague-Dawley rats were studied 21 weeks after aortocaval fistula (ACF) or sham surgery. Echocardiography revealed decreased fractional shortening accompanied by increased LV chamber diameter and decreased eccentric dilatation index at end-stage ACF compared to sham. Hemodynamic measurements showed a decrease in the slope of end-systolic pressure–volume relationship, indicating systolic dysfunction. Isolated LV myocytes from ACF exhibited decreased peak sarcomere shortening and kinetics. Both Ca2 + transient amplitude and kinetics were increased in ACF myocytes, with no change under the integrated Ca2 + curves relating to contraction and relaxation phases. Increases in ryanodine receptor and phospholamban phosphorylation, along with a decrease in SERCA2 levels, were observed in ACF. These changes were associated with decreased expression of β-myosin heavy chain, cardiac troponin I and cardiac myosin binding protein-C. In vivo inotropic responses to β-adrenergic stimulation were attenuated in ACF. Interestingly, ACF myocytes exhibited a similar peak shortening to those of sham in response to a β-adrenergic agonist. The protein expression of the gap junction protein connexin-43 was decreased, although its phosphorylation at Ser-368 increased. These changes were associated with alterations in Src and ZO-1. In summary, these data suggest that the disconnect in β-adrenergic responsiveness between in vivo and in vitro conditions may be associated with altered myofilament Ca2 + sensitivity and connexin-43 degradation.
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cardiovascular remodeling in response to long term exposure to fine particulate matter air pollution
Circulation-heart Failure, 2012Co-Authors: Loren E Wold, Pamela A Lucchesi, Zhekang Ying, Kirk R Hutchinson, Markus Velten, Matthew W Gorr, Christina Velten, Dane J Youtz, Aixia Wang, Qinghua SunAbstract:Background—Air pollution is a pervasive environmental health hazard that occurs over a lifetime of exposure in individuals from many industrialized societies. However, studies have focused primarily on exposure durations that correspond to only a portion of the lifespan. We therefore tested the hypothesis that exposure over a considerable portion of the lifespan would induce maladaptive cardiovascular responses. Methods and Results—C57BL/6 male mice were exposed to concentrated ambient particles <2.5 µm (particulate matter, PM or PM2.5) or filtered air (FA), 6 h/d, 5 d/wk, for 9 months. Assessment of cardiac contractile function, coronary arterial flow reserve, Isolated Cardiomyocyte function, expression of hypertrophic markers, calcium handling proteins, and cardiac fibrosis were then performed. Mean daily concentrations of PM2.5 in the exposure chamber versus ambient daily PM2.5 concentration at the study site were 85.3 versus 10.6 µg/m3 (7.8-fold concentration), respectively. PM2.5 exposure resulted in...
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left ventricular eccentric remodeling and matrix loss are mediated by bradykinin and precede Cardiomyocyte elongation in rats with volume overload
Journal of the American College of Cardiology, 2007Co-Authors: Thomas D. Ryan, Ahsan Husain, Emily C Rothstein, Inmaculada Aban, Jose A. Tallaj, Pamela A Lucchesi, Louis J DellitaliaAbstract:Objectives We hypothesized that left ventricular (LV) remodeling and matrix loss in volume overload (VO) are mediated by bradykinin (BK) and exacerbated by chronic angiotensin-converting enzyme (ACE) inhibition. Background Chronic ACE inhibition increases anti-fibrotic BK and does not attenuate LV remodeling in pure VO. The relative contribution of changes in extracellular matrix versus Cardiomyocyte elongation in acute and chronic LV chamber remodeling during VO is unknown. Methods Echocardiography, LV collagen content, and Isolated Cardiomyocytes were studied in rats after aortocaval fistula (ACF) of 12 h, 2 and 5 days, and 4, 8, and 15 weeks. We also studied ACF rats after BK 2 receptor (BK 2 R) blockade (2 days) or ACE inhibition (4 weeks). Results At 2 days after ACF, LV end-diastolic dimension (LVEDD)/wall thickness was increased, and LV interstitial collagen was decreased by 50% without Cardiomyocyte elongation. The BK 2 R blockade prevented collagen loss and normalized LVEDD/wall thickness. From 4 to 15 weeks after ACF, interstitial collagen decreased by 30% and left ventricular end-systolic (LVES) dimension increased despite normal LVES pressure and Isolated Cardiomyocyte function. The ACE inhibition did not decrease LVEDD/wall thickness, further decreased LV interstitial collagen, and did not improve LV fractional shortening despite decreased LVES pressure. Conclusions Immediately after ACF induction, eccentric LV remodeling is mediated by interstitial collagen loss without Cardiomyocyte elongation. Acute BK 2 R blockade prevents eccentric LV remodeling and improves function. Chronic ACE inhibition does not prevent eccentric LV remodeling or improve function. These findings suggest that ACE inhibitor-mediated increase in LV BK exacerbates matrix loss and explains why ACE inhibition is ineffective in VO.
Kirk R Hutchinson - One of the best experts on this subject based on the ideXlab platform.
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in vivo and in vitro cardiac responses to beta adrenergic stimulation in volume overload heart failure
Journal of Molecular and Cellular Cardiology, 2013Co-Authors: Kirk R Hutchinson, Anuradha Guggilam, Aaron T West, Amy P Kelly, Maarten L Galantowicz, Amy J Davidoff, Sakthivel Sadayappan, Pamela A LucchesiAbstract:Abstract Hearts in volume overload (VO) undergo progressive ventricular hypertrophy resulting in chronic heart failure that is unresponsive to β-adrenergic agonists. This study compared left ventricular (LV) and Isolated Cardiomyocyte contractility and β-adrenergic responsiveness in rats with end-stage VO heart failure (HF). Adult male Sprague-Dawley rats were studied 21 weeks after aortocaval fistula (ACF) or sham surgery. Echocardiography revealed decreased fractional shortening accompanied by increased LV chamber diameter and decreased eccentric dilatation index at end-stage ACF compared to sham. Hemodynamic measurements showed a decrease in the slope of end-systolic pressure–volume relationship, indicating systolic dysfunction. Isolated LV myocytes from ACF exhibited decreased peak sarcomere shortening and kinetics. Both Ca2 + transient amplitude and kinetics were increased in ACF myocytes, with no change under the integrated Ca2 + curves relating to contraction and relaxation phases. Increases in ryanodine receptor and phospholamban phosphorylation, along with a decrease in SERCA2 levels, were observed in ACF. These changes were associated with decreased expression of β-myosin heavy chain, cardiac troponin I and cardiac myosin binding protein-C. In vivo inotropic responses to β-adrenergic stimulation were attenuated in ACF. Interestingly, ACF myocytes exhibited a similar peak shortening to those of sham in response to a β-adrenergic agonist. The protein expression of the gap junction protein connexin-43 was decreased, although its phosphorylation at Ser-368 increased. These changes were associated with alterations in Src and ZO-1. In summary, these data suggest that the disconnect in β-adrenergic responsiveness between in vivo and in vitro conditions may be associated with altered myofilament Ca2 + sensitivity and connexin-43 degradation.
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cardiovascular remodeling in response to long term exposure to fine particulate matter air pollution
Circulation-heart Failure, 2012Co-Authors: Loren E Wold, Pamela A Lucchesi, Zhekang Ying, Kirk R Hutchinson, Markus Velten, Matthew W Gorr, Christina Velten, Dane J Youtz, Aixia Wang, Qinghua SunAbstract:Background—Air pollution is a pervasive environmental health hazard that occurs over a lifetime of exposure in individuals from many industrialized societies. However, studies have focused primarily on exposure durations that correspond to only a portion of the lifespan. We therefore tested the hypothesis that exposure over a considerable portion of the lifespan would induce maladaptive cardiovascular responses. Methods and Results—C57BL/6 male mice were exposed to concentrated ambient particles <2.5 µm (particulate matter, PM or PM2.5) or filtered air (FA), 6 h/d, 5 d/wk, for 9 months. Assessment of cardiac contractile function, coronary arterial flow reserve, Isolated Cardiomyocyte function, expression of hypertrophic markers, calcium handling proteins, and cardiac fibrosis were then performed. Mean daily concentrations of PM2.5 in the exposure chamber versus ambient daily PM2.5 concentration at the study site were 85.3 versus 10.6 µg/m3 (7.8-fold concentration), respectively. PM2.5 exposure resulted in...
Anuradha Guggilam - One of the best experts on this subject based on the ideXlab platform.
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in vivo and in vitro cardiac responses to beta adrenergic stimulation in volume overload heart failure
Journal of Molecular and Cellular Cardiology, 2013Co-Authors: Kirk R Hutchinson, Anuradha Guggilam, Aaron T West, Amy P Kelly, Maarten L Galantowicz, Amy J Davidoff, Sakthivel Sadayappan, Pamela A LucchesiAbstract:Abstract Hearts in volume overload (VO) undergo progressive ventricular hypertrophy resulting in chronic heart failure that is unresponsive to β-adrenergic agonists. This study compared left ventricular (LV) and Isolated Cardiomyocyte contractility and β-adrenergic responsiveness in rats with end-stage VO heart failure (HF). Adult male Sprague-Dawley rats were studied 21 weeks after aortocaval fistula (ACF) or sham surgery. Echocardiography revealed decreased fractional shortening accompanied by increased LV chamber diameter and decreased eccentric dilatation index at end-stage ACF compared to sham. Hemodynamic measurements showed a decrease in the slope of end-systolic pressure–volume relationship, indicating systolic dysfunction. Isolated LV myocytes from ACF exhibited decreased peak sarcomere shortening and kinetics. Both Ca2 + transient amplitude and kinetics were increased in ACF myocytes, with no change under the integrated Ca2 + curves relating to contraction and relaxation phases. Increases in ryanodine receptor and phospholamban phosphorylation, along with a decrease in SERCA2 levels, were observed in ACF. These changes were associated with decreased expression of β-myosin heavy chain, cardiac troponin I and cardiac myosin binding protein-C. In vivo inotropic responses to β-adrenergic stimulation were attenuated in ACF. Interestingly, ACF myocytes exhibited a similar peak shortening to those of sham in response to a β-adrenergic agonist. The protein expression of the gap junction protein connexin-43 was decreased, although its phosphorylation at Ser-368 increased. These changes were associated with alterations in Src and ZO-1. In summary, these data suggest that the disconnect in β-adrenergic responsiveness between in vivo and in vitro conditions may be associated with altered myofilament Ca2 + sensitivity and connexin-43 degradation.
Jia Liu - One of the best experts on this subject based on the ideXlab platform.
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dichloroacetate ameliorates cardiac dysfunction caused by ischemic insults through ampk signal pathway not only shifts metabolism
Toxicological Sciences, 2019Co-Authors: Jia Liu, Nanhu Quan, Thomas Rousselle, Mulchand S PatelAbstract:Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), regulates substrate metabolism in the heart. AMP-activated protein kinase (AMPK) is an age-related energy sensor that protects the heart from ischemic injury. This study aims to investigate whether DCA can protect the heart from ischemic injury through the AMPK signaling pathway. Young (3-4 months) and aged (20-24 months) male C57BL/6J mice were subjected to ligation of the left anterior descending coronary artery (LAD) for an in vivo ischemic model. The systolic function of the hearts was significantly decreased in both young and aged mice after 45 min of ischemia and 24 h of reperfusion. DCA treatment significantly improved cardiac function in both young and aged mice. The myocardial infarction analysis demonstrated that DCA treatment significantly reduced the infarction size caused by ischemia/reperfusion (I/R) in both young and aged mice. The Isolated-Cardiomyocyte experiments showed that DCA treatment ameliorated contractile dysfunction and improved the intracellular calcium signal of Cardiomyocytes under hypoxia/reoxygenation (H/R) conditions. These cardioprotective functions of DCA can be attenuated by inhibiting AMPK activation. Furthermore, the metabolic measurements with an ex vivo working heart system demonstrated that the effects of DCA treatment on modulating the metabolic shift response to ischemia and reperfusion stress can be attenuated by inhibiting AMPK activity. The immunoblotting results showed that DCA treatment triggered cardiac AMPK signaling pathway by increasing the phosphorylation of AMPK's upstream kinase liver kinase B1 (LKB1) under both sham operations and I/R conditions. Thus, except from modulating metabolism in hearts, the cardioprotective function of DCA during I/R was mediated by the LKB1-AMPK pathway.
