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1.  c-kit-Positive Cardiac Stem Cells Nested in Hypoxic Niches are Activated by Stem Cell Factor Reversing the Aging Myopathy 
Circulation research  2013;114(1):41-55.
Hypoxia favors stem cell quiescence, while normoxia is required for their activation; but whether cardiac stem cell (CSC) function is regulated by the hypoxic/normoxic state of the cell is currently unknown.
A balance between hypoxic and normoxic CSCs may be present in the young heart, although this homeostatic control may be disrupted with aging. Defects in tissue oxygenation occur in the old myocardium, and this phenomenon may expand the pool of hypoxic CSCs, which are no longer involved in myocyte renewal.
Methods and Results
Here we show that the senescent heart is characterized by an increased number of quiescent CSCs with intact telomeres that cannot reenter the cell cycle and form a differentiated progeny. Conversely, myocyte replacement is controlled only by frequently dividing CSCs with shortened telomeres; these CSCs generate a myocyte population that is chronologically young but phenotypically old. Telomere dysfunction dictates their actual age and mechanical behavior. However, the residual subset of quiescent young CSCs can be stimulated in situ by stem cell factor reversing the aging myopathy.
Our findings support the notion that strategies targeting CSC activation and growth interfere with the manifestations of myocardial aging in an animal model. Although caution has to be exercised in the translation of animal studies to human beings, our data strongly suggests that a pool of functionally-competent CSCs persists in the senescent heart and this stem cell compartment can promote myocyte regeneration effectively, correcting partly the aging myopathy.
PMCID: PMC3959163  PMID: 24170267
Cardiac stem cells; hypoxia; myocardial aging; stem cell factor
2.  An Unsuspected Property of Natriuretic Peptides: Promotion of Calcium-Dependent Catecholamine Release via Protein Kinase G-Mediated Phosphodiesterase Type 3 Inhibition 
Circulation  2011;125(2):298-307.
Although natriuretic peptides are considered cardioprotective, clinical heart failure trials with recombinant BNP (nesiritide) failed to prove it. Unsuspected proadrenergic effects might oppose the anticipated benefits of natriuretic peptides.
Methods and Results
We investigated whether natriuretic peptides induce catecholamine release in isolated hearts, sympathetic nerve endings (cardiac synaptosomes) and PC12 cells bearing a sympathetic neuron phenotype. Perfusion of isolated guinea pig hearts with BNP elicited a 3-fold increase in norepinephrine release which doubled in ischemia/reperfusion conditions. BNP and ANP also released norepinephrine from cardiac synaptosomes and dopamine from nerve-growth-factor-differentiated PC12 cells in a concentration-dependent manner. These catecholamine-releasing effects were associated with an increase in intracellular calcium, and abolished by blockade of calcium channels and calcium transients, demonstrating a calcium-dependent exocytotic process. Activation of the guanylyl cyclase-cGMP-protein-kinase-G system with nitroprusside or membrane-permeant cGMP analogs mimicked the proexocytotic effect of natriuretic peptides, an action associated with an increase in intracellular cAMP and protein-kinase-A activity. cAMP enhancement resulted from an inhibition of phosphodiesterase-type-3-induced cAMP hydrolysis. Collectively, these findings indicate that, by inhibiting phosphodiesterase-type-3, natriuretic peptides sequentially enhance intracellular cAMP levels, protein-kinase-A activity, intracellular calcium and catecholamine exocytosis.
Our results show that natriuretic peptides, at concentrations likely to be reached at cardiac sympathetic nerve endings in advanced congestive heart failure, promote norepinephrine release via a protein-kinase-G-induced inhibition of phosphodiesterase-type-3-mediated cAMP hydrolysis. We propose that this proadrenergic action may counteract the beneficial cardiac and hemodynamic effects of natriuretic peptides, and thus explain the ineffectiveness of nesiritide as a cardiac failure medication.
PMCID: PMC3287346  PMID: 22158783
catecholamines; heart failure; natriuretic peptides
3.  Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells 
Circulation  2010;122(8):771-781.
Renin released by ischemia/reperfusion (I/R) from cardiac mast cells activates a local renin-angiotensin system (RAS). This exacerbates norepinephrine release and reperfusion arrhythmias (VT/VF), making RAS a new therapeutic target in myocardial ischemia.
Methods and Results
We investigated whether ischemic preconditioning (IPC) prevents cardiac RAS activation in guinea-pig hearts ex-vivo. When I/R (20-min ischemia/30-min reperfusion) was preceded by IPC (2×5-min I/R cycles), renin and norepinephrine release and VT/VF duration were markedly decreased, a cardioprotective anti-RAS effect. Activation and blockade of adenosine A2b/A3-receptors, and activation and inhibition of PKCε, mimicked and prevented, respectively, the anti-RAS effects of IPC. Moreover, activation of A2b/A3-receptors, or activation of PKCε, prevented degranulation and renin release elicited by peroxide in cultured mast cells (HMC-1). Activation and inhibition of mitochondrial aldehyde dehydrogenase type-2 (ALDH2) also mimicked and prevented, respectively, the cardioprotective anti-RAS effects of IPC. Furthermore, ALDH2 activation inhibited degranulation and renin release by reactive aldehydes in HMC-1. Notably, PKCε and ALDH2 were both activated by A2b/A3-receptor stimulation in HMC-1, and PKCε inhibition prevented ALDH2 activation.
The results uncover a signaling cascade initiated by A2b/A3-receptors, which triggers PKCε-mediated ALDH2 activation in cardiac mast cells, contributing to IPC-induced cardioprotection by preventing mast-cell renin release and the dysfunctional consequences of local RAS activation. Thus, unlike classical IPC where cardiac myocytes are the main target, cardiac mast cells are the critical site at which the cardioprotective anti-RAS effects of IPC develop.
PMCID: PMC2927811  PMID: 20697027
Renin; Ischemia; Reperfusion; Norepinephrine; Arrhythmia

Results 1-3 (3)