American journal of physiology. Heart and circulatory physiology
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Am. J. Physiol. Heart Circ. Physiol. · Aug 2018
Apelin and APJ orchestrate complex tissue-specific control of cardiomyocyte hypertrophy and contractility in the hypertrophy-heart failure transition.
The G protein-coupled receptor APJ is a promising therapeutic target for heart failure. Constitutive deletion of APJ in the mouse is protective against the hypertrophy-heart failure transition via elimination of ligand-independent, β-arrestin-dependent stretch transduction. However, the cellular origin of this stretch transduction and the details of its interaction with apelin signaling remain unknown. ⋯ These data establish that APJ stretch transduction is mediated specifically by myocardial APJ, that APJ is necessary for stretch-induced increases in contractility, and that apelin opposes APJ's stretch-mediated hypertrophy signaling by lowering Ca2+ transients while maintaining contractility through myofilament Ca2+ sensitization. These findings underscore apelin's unique potential as a therapeutic agent that can simultaneously support cardiac function and protect against the hypertrophy-heart failure transition. NEW & NOTEWORTHY These data address fundamental gaps in our understanding of apelin-APJ signaling in heart failure by localizing APJ's ligand-independent stretch sensing to the myocardium, identifying a novel mechanism of apelin-APJ inotropy via myofilament Ca2+ sensitization, and identifying potential mitigating effects of apelin in APJ stretch-induced hypertrophic signaling.
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Am. J. Physiol. Heart Circ. Physiol. · Jun 2018
Comparative StudyVagal stimulation mimics preconditioning and postconditioning of ischemic myocardium in mice by activating different protection mechanisms.
Vagal stimulation (VS) during myocardial ischemia and reperfusion has beneficial effects. However, it is not known whether short-term VS applied before ischemia or at the onset of reperfusion protects the ischemic myocardium. This study was designed to determine whether short-term VS applied before ischemia or at the onset of reperfusion reduces myocardial infarct size (IS), mimicking classic preconditioning and postconditioning. ⋯ In conclusion, pVS and rVS reduced IS by different mechanisms: pVS activated the Akt/GSK-3β muscarinic pathway, whereas rVS activated α7-nicotinic acetylcholine receptors and JAK2, independently of the cholinergic anti-inflammatory pathway. NEW & NOTEWORTHY Our data suggest, for the first time, that vagal stimulation applied briefly either before ischemia or at the beginning of reperfusion mimics classic preconditioning and postconditioning and reduces myocardial infarction, activating different mechanisms. We also infer an important role of α7-nicotinic receptors for myocardial protection independent of the cholinergic anti-inflammatory pathway.
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Am. J. Physiol. Heart Circ. Physiol. · Apr 2018
Maximal strength training-induced improvements in forearm work efficiency are associated with reduced blood flow.
Maximal strength training (MST) improves work efficiency. However, since blood flow is greatly dictated by muscle contractions in arms during exercise and vascular conductance is lower, it has been indicated that arms rely more upon adapting oxygen extraction than legs in response to the enhanced work efficiency. Thus, to investigate if metabolic and vascular responses are arm specific, we used Doppler-ultrasound and a catheter placed in the subclavian vein to measure blood flow and the arteriovenous oxygen difference during steady-state work in seven young men [24 ± 3 (SD) yr] following 6 wk of handgrip MST. ⋯ NEW & NOTEWORTHY Maximal strength training increases skeletal muscle work efficiency. Oxygen extraction has been indicated to be the adapting component with this increased work efficiency in arms. However, we document that decreased blood flow, achieved by blood velocity reduction, is the adapting mechanism responding to the improved aerobic metabolism in the forearm musculature.
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Am. J. Physiol. Heart Circ. Physiol. · Mar 2018
Protective effects of the mechanistic target of rapamycin against excess iron and ferroptosis in cardiomyocytes.
Clinical studies have suggested that myocardial iron is a risk factor for left ventricular remodeling in patients after myocardial infarction. Ferroptosis has recently been reported as a mechanism of iron-dependent nonapoptotic cell death. However, ferroptosis in the heart is not well understood. ⋯ NEW & NOTEWORTHY Ferroptosis has recently been reported as a new form of iron-dependent nonapoptotic cell death. However, ferroptosis in the heart is not well characterized. Using cultured adult mouse cardiomyocytes, we demonstrated that the mechanistic target of rapamycin plays an important role in protecting cardiomyocytes against excess iron and ferroptosis.
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Am. J. Physiol. Heart Circ. Physiol. · Mar 2018
Exercise facilitates early recognition of cardiac and vascular remodeling in chronic thromboembolic pulmonary hypertension in swine.
Chronic thromboembolic pulmonary hypertension (CTEPH) develops in 4% of patients after pulmonary embolism and is accompanied by an impaired exercise tolerance, which is ascribed to the increased right ventricular (RV) afterload in combination with a ventilation/perfusion (V/Q) mismatch in the lungs. The present study aimed to investigate changes in arterial Po2 and hemodynamics in response to graded treadmill exercise during development and progression of CTEPH in a novel swine model. Swine were chronically instrumented and received multiple pulmonary embolisms by 1) microsphere infusion (Spheres) over 5 wk, 2) endothelial dysfunction by administration of the endothelial nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (L-NAME) for 7 wk, 3) combined pulmonary embolisms and endothelial dysfunction (L-NAME + Spheres), or 4) served as sham-operated controls (sham). ⋯ Exercise increased RV afterload, exacerbated the V/Q mismatch, and unmasked RV dysfunction. NEW & NOTEWORTHY Here, we present the first double-hit chronic thromboembolic pulmonary hypertension swine model. We show that embolization as well as endothelial dysfunction is required to induce sustained pulmonary hypertension, which is accompanied by altered exercise hemodynamics and an exacerbated ventilation/perfusion mismatch during exercise.