In this Issue
July 2016; volume 311, issue 1
CALL FOR PAPERS | Cardiovascular Epigenetics: Phenotypes and Mechanisms
CALL FOR PAPERS | Cardiovascular Mitochondria and Redox Control in Health and Disease
- Discordant signaling and autophagy response to fasting in hearts of obese mice: Implications for ischemia tolerance
Developing metabolic syndrome leads to impaired cardiac autophagy and larger infarcts after myocardial ischemia and reperfusion. Quantitative proteomic analysis of hearts from diet-induced obese mice subjected to fasting stress reveal global changes in the proteome related to metabolism, redox, vesicular, and structural homeostasis that may increase vulnerability to ischemia-reperfusion injury.
CALL FOR PAPERS | Plasma Membrane Integrity in Cardiovascular Physiology and Pathophysiology
- Small membrane permeable molecules protect against osmotically induced sealing of t-tubules in mouse ventricular myocytes
The t-tubular network is essential for efficient excitation-contraction coupling but its integrity is compromised in various pathophysiological conditions. The current study shows that DMSO and other small membrane permeable molecules are able to provide significant protection to the t-tubule network against hyposmotic stress.
CALL FOR PAPERS | Quantitative Analyses of Coronary Vascular and Cardiac Mechanics in Health and Disease
- Influence of anatomical dominance and hypertension on coronary conduit arterial and microcirculatory flow patterns: a multiscale modeling study
Using a novel multiscale model of the human coronary circulation situated in a closed-loop cardiovascular model, we performed the first comprehensive analysis of the effects of left or right coronary arterial dominance on regional conduit arterial and microvascular arterial/venous flow patterns under normotensive conditions, and with systemic or pulmonary hypertension.
CALL FOR PAPERS | Small Vessels-Big Problems: Novel Insights into Microvascular Mechanisms of Diseases
- Selective subepicardial localization of monocyte subsets in response to progressive coronary artery constriction
This study characterizes monocyte subpopulations in rabbits based on the expression of the L-selectin receptor CD62L. We noted selective subepicardial homing of both monocyte groups in response to coronary artery occlusion, with a larger proportion of classical monocytes. These results were supported by different migratory properties of each monocyte group.
Cardiac Excitation and Contraction
- Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca2+-sensitive myofilaments
We show here, as proof-of-concept, small-molecule-based Ca2+ desensitization for sarcomere neutralization therapy in models of acquired and inherited hyper-Ca2+-sensitive disease states. At both the cellular and organ level, contractile dysfunction in both models was acutely corrected with W7, a sarcomere Ca2+ desensitizer.
- High-throughput drug profiling with voltage- and calcium-sensitive fluorescent probes in human iPSC-derived cardiomyocytes
We describe 96-well recording of synchronous electrical activities from spontaneously beating human induced pluripotent stem cell-derived cardiomyocyte monolayers using FluoVolt as a substitute for patch-clamp measurements, validated with reference pharmacological compounds to demonstrate the usefulness of the approach.
- Electrochemical Na+ and Ca2+ gradients drive coupled-clock regulation of automaticity of isolated rabbit sinoatrial nodal pacemaker cells
We discovered how the coupling of Na+ and Ca2+ electrochemical gradients regulates cross talk of surface membrane and Ca2+ clocks to regulate automaticity via the coupled-clock system; our numerical model simulations detected “a window” of system parameters for this effect on normal automaticity that borders on abnormal automaticity.
- R-CEPIA1er as a new tool to directly measure sarcoplasmic reticulum [Ca] in ventricular myocytes
This is the first study that characterizes the novel fluorescent biosensor R-CEPIA1er that allows dynamic measurement of calcium within the sarcoplasmic reticulum in living cardiomyocytes. This novel, powerful tool will be essential in providing important new information regarding calcium regulation in healthy and diseased heart.
Integrative Cardiovascular Physiology and Pathophysiology
- Females have greater left ventricular twist mechanics than males during acute reductions to preload
This is the first study to demonstrate sex differences in left ventricular twist mechanics during acute preload challenges. Our data demonstrate that females utilize larger left ventricular twist and faster untwisting velocity than males to maintain mean arterial pressure during severe reductions to preload.
- Distinct right ventricle remodeling in response to pressure overload in the rat
Right ventricular (RV) adaptation to pressure overload differs depending on the degree of overload. In this work we present a thorough analysis of adaptive and maladaptive remodeling of the RV in response to pulmonary artery banding, allowing for future research to target a specific stage of RV remodeling.
- The α11 integrin mediates fibroblast–extracellular matrix–cardiomyocyte interactions in health and disease
We demonstrate that the α11β1 (α11) integrin is critical for ECM accumulation in response to diabetes in vivo. Furthermore, we show that deletion of the fibroblast-specific α11 integrin disrupts normal cardiac function and cardiomyocyte morphology. These findings emphasize the importance of integrin fibroblast–ECM–cardiomyocyte interactions in health and disease.
- A myosin activator improves actin assembly and sarcomere function of human-induced pluripotent stem cell-derived cardiomyocytes with a troponin T point mutation
Cardiac myocytes were derived from induced pluripotent stem cells from normal and family members expressing a mutant cardiac troponin T linked to dilated cardiomyopathy. Shortening, actin content and assembly dynamics were depressed in the severely affected mutant but reversed by a myosin activation reagent. Sarcomeric isoform composition was fetal/neonatal.
- Differential effects of nebivolol vs. metoprolol on microvascular function in hypertensive humans
We identified a deleterious effect of chronic administration of metoprolol on microvascular function during handgrip in hypertensive patients, which was not observed with nebivolol. The impaired muscle capillary recruitment during exercise may predispose to development of exercise intolerance.
- Chronic vagal nerve stimulation prevents high-salt diet-induced endothelial dysfunction and aortic stiffening in stroke-prone spontaneously hypertensive rats
This study demonstrates that chronic vagal nerve stimulation slows progression of endothelial dysfunction and aortic stiffening in stroke-prone spontaneously hypertensive rats on high-salt diet. Interleukin-6 and interleukin-10 serum levels correlated with endothelial function, suggesting a mechanistic link between the protective vascular effects of vagal nerve stimulation and inflammation.
Muscle Mechanics and Ventricular Function
- Sex dimorphisms of crossbridge cycling kinetics in transgenic hypertrophic cardiomyopathy mice
We illustrate sex dimorphisms in crossbridge kinetics where male hypertrophic cardiomyopathy hearts displayed an increased while female hypertrophic cardiomyopathy hearts displayed a decreased tension cost. In addition, we have found sex- and mutation-dependent differences in cardiac remodeling at the morphometric, histological, and cellular level.
Vascular Biology and Microcirculation
- Disrupted NOS signaling in lymphatic endothelial cells exposed to chronically increased pulmonary lymph flow
Lymphatic endothelial cells, exposed to chronically elevated pulmonary lymph flow in a model of congenital heart disease with increased pulmonary blood flow, demonstrate disrupted nitric oxide (NO) signaling. Specifically, they have altered NO synthase expression and activity that result in increased accumulation of reactive oxygen species and decreased bioavailable NO.
- Context-dependent effects of SOCS3 in angiotensin II-induced vascular dysfunction and hypertension in mice: mechanisms and role of bone marrow-derived cells
This study provides new mechanistic insight into the impact of suppressor of cytokine signaling 3 (SOCS3) on the vasculature, including divergent effects depending on the source of angiotensin II (Ang II) (local vs. systemic). Bone marrow-derived cells deficient in SOCS3 protect against systemic Ang II-induced vascular dysfunction.
- Vascular smooth muscle desensitization in rabbit epigastric and mesenteric arteries during hemorrhagic shock
Following initial homeostatic compensation, the “shock” phase of hemorrhage involves persistent vasoconstrictor-resistant vasodilation. This study suggests that such vascular hyporeactivity is explained by intrinsic vascular muscle desensitization caused by compensatory elevations in vasoconstrictors. Further investigations into molecular targets that block desensitization may reverse vasoconstrictor insensitivity allowing reanimation of shock victims.
- The endothelial glycocalyx promotes homogenous blood flow distribution within the microvasculature
This study identifies a microfluidic-based mechanism for the abnormal distribution of microvascular blood flow observed under conditions of glycocalyx degradation and suggests a causal role for glycocalyx degradation in impaired tissue perfusion and oxygenation in several nominally unrelated disease states.
- Purinergic dysregulation in pulmonary hypertension
This is the first study to report that deletion of CD39 results in high pulmonary arterial pressures and increases in the intravascular ATP/adenosine ratio and pulmonary vascular P2X1 receptors. It also shows that reconstitution of ectonucleotidase activity lessens, and P2X1 receptor blocking eliminates, elevated pulmonary arterial pressures.
- Uridine adenosine tetraphosphate acts as a proangiogenic factor in vitro through purinergic P2Y receptors
Novel findings include 1) uridine adenosine tetraphosphate (Up4A) promotes angiogenesis in vitro in a tree-dimensional matrix human pericyte-endothelial cell coculture system. 2) Up4A increases expression of P2YRs (P2Y2R, P2Y4R, and P2Y6R) and proangiogenic factors. The proangiogenic properties of Up4A are mediated by activation of pyrimidine-favored P2YRs but not P2XR or P1Rs.
- Prolonged sitting-induced leg endothelial dysfunction is prevented by fidgeting
This study reveals that the simple behavior of fidgeting is sufficient to counteract the detrimental effects of prolonged sitting on leg endothelial function. Thus, we provide the first evidence that the unfavorable vascular effects of sitting are avoidable with small amounts of leg movement while seated for an extended period.
- Matrix metalloproteinase-2 in oncostatin M-induced sarcomere degeneration in cardiomyocytes
The cytokine oncostatin-M (OSM) can induce cardiomyocyte dedifferentiation, associated with sarcomere degeneration. We find that OSM treatment of cardiomyocytes increases matrix metalloproteinase-2 (MMP-2) expression and activity and that pharmaceutical inhibition of MMP-2 prevents OSM-induced sarcomere degeneration. This suggests a previously unknown role for MMP-2 in modulation of sarcomere structure and integrity.