Biomedical subjects

Michael V G Latronico

Publications and source records attributed to Michael V G Latronico.

6 recordsLinked to original sources

PubMed2004

Isolation and expansion of adult cardiac stem cells from human and murine heart.

Cardiac myocytes have been traditionally regarded as terminally differentiated cells that adapt to increased work and compensate for disease exclusively through hypertrophy. However, in the past few years, compelling evidence has accumulated suggesting that the heart has regenerative potential. Recent studies have even surmised the existence of resident cardiac stem cells, endothelial cells generating cardiomyocytes by cell contact or extracardiac progenitors for cardiomyocytes, but these findings are still controversial. We describe the isolation of undifferentiated cells that grow as self-adherent clusters (that we have termed "cardiospheres") from subcultures of postnatal atrial or ventricular human biopsy specimens and from murine hearts. These cells are clonogenic, express stem and endothelial progenitor cell antigens/markers, and appear to have the properties of adult cardiac stem cells. They are capable of long-term self-renewal and can differentiate in vitro and after ectopic (dorsal subcutaneous connective tissue) or orthotopic (myocardial infarction) transplantation in SCID beige mouse to yield the major specialized cell types of the heart: myocytes (ie, cells demonstrating contractile activity and/or showing cardiomyocyte markers) and vascular cells (ie, cells with endothelial or smooth muscle markers).

Adolescent↗

PubMed2004

Regulation of cell size and contractile function by AKT in cardiomyocytes.

AKT is a serine-threonine kinase involved in several different cellular functions, including the control of cell size and the regulation of survival and metabolism. Many studies have demonstrated that AKT also plays a critical role in the homeostasis of the cardiomyocyte. In these cells, AKT is activated by upstream molecules such as beta-adrenergic receptor, insulin-like growth factor-1 or insulin receptor, through PI3K alpha; whereas its activation is inhibited by the PTEN molecule. Downstream targets of AKT in the cardiomyocyte include glycogen-synthase kinase-3 beta and S6 kinase. Major effects of AKT activation in the cardiomyocyte are increase in cell size, prevention of apoptosis, and regulation of glucose metabolism. Interestingly, the AKT-dependent hypertrophic pathway is distinct from that activated by MAPKs. In fact, overexpression of AKT does not lead to MAPK activation. Our group has shown, moreover, that AKT exerts a positive effect on both inotropism and relaxation. In fact, mice overexpressing the E40K mutant of AKT in the heart showed improved cardiac function. Thus, AKT increases both cell size through the S6 kinase pathway and inotropism through the functional regulation of critical Ca(2+)-handling proteins. Therefore, AKT is a critical mediator of physiological hypertrophy.

Animals↗

PubMed2003

Cardiomyocytes.

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Animals↗

PubMed2002

Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice.

The serine-threonine kinase Akt seems to be central in mediating stimuli from different classes of receptors. In fact, both IGF-1 and IL6-like cytokines induce hypertrophic and antiapoptotic signals in cardiomyocytes through PI3K-dependent Akt activation. More recently, it was shown that Akt is involved also in the hypertrophic and antiapoptotic effects of beta-adrenergic stimulation. Thus, to determine the effects of Akt on cardiac function in vivo, we generated a model of cardiac-specific Akt overexpression in mice. Transgenic mice were generated by using the E40K, constitutively active mutant of Akt linked to the rat alpha-myosin heavy chain promoter. The effects of cardiac-selective Akt overexpression were studied by echocardiography, cardiac catheterization, histological and biochemical techniques. We found that Akt overexpression produced cardiac hypertrophy at the molecular and histological levels, with a significant increase in cardiomyocyte cell size and concentric LV hypertrophy. Akt-transgenic mice also showed a remarkable increase in cardiac contractility compared with wild-type controls as demonstrated by the analysis of left ventricular (dP/dt(max)) in an invasive hemodynamic study, although with graded dobutamine infusion, the maximum response was not different from that in controls. Diastolic function, evaluated by left ventricular dP/dt(min), was not affected at rest but was impaired during graded dobutamine infusion. Isoproterenol-induced cAMP levels, beta-adrenergic receptor (beta-AR) density, and beta-AR affinity were not altered compared with control mice. Moreover, studies on signaling pathway activation from myocardial extracts demonstrated that glycogen synthase kinase3-beta is phosphorylated, whereas p42/44 mitogen-activated protein kinases is not, indicating that Akt induces hypertrophy in vivo by activating the glycogen synthase kinase3-beta/GATA 4 pathway. In summary, our results not only demonstrate that Akt regulates cardiomyocyte cell size in vivo, but, importantly, show that Akt modulates cardiac contractility in vivo without directly affecting beta-AR signaling capacity.

Animals↗

PubMed2002

Th1 and Th2 cytokines exert regulatory effects upon islet microvascular areas in the NOD mouse.

In this study, we show that intra- and peri-islet microvascular areas undergo different changes during the islet inflammation in the nonobese diabetes-prone female mice. Actually, although the islet vascular area (IVA) considerably decreases while the infiltration progresses, at 15 weeks of age, the peri-islet vascular bed is unexpectedly and significantly increased. On the contrary, the intra-IVA is significantly decreased, due to vessel dilation. Later, by 20-25 weeks of age, a decrease of both IVA occur, due to a significant islet beta cell loss. Moreover, a dramatic fall of natural free radical scavenger values, which, in turn, exert an influence upon vessels, is observed. These effects are completely counteracted by the administration of IL-4, a Th2 protective cytokine; IL-10, another putative Th2 cytokine, exerts direct effects upon endothelial cell (EC) function, as shown by the increase of endothelial nitric oxide synthase (eNOS) mRNA transcripts and by the release of endothelial NO which, in turn, exert vasodilatory effects; moreover, this cytokine significantly upregulates adhesion molecules on endothelia. On the other hand, IL-1beta, a Th1 proinflammatory cytokine, dramatically increases nitrite and nitrate levels, as well as inducible nitric oxide synthase (iNOS) transcripts and also upregulates islet ICAM-1 expression as well as circulating ICAM-1 levels. Taken together, our findings clearly show that cytokines and islet endothelia are directly involved in the pathophysiology of the disease. Their reciprocal influence gives new insight to understand the role of microvasculature during islet beta cell attack.

Animals↗

PubMed2002

TNF-alpha signal transduction in rat neonatal cardiac myocytes: definition of pathways generating from the TNF-alpha receptor.

Cardiomyocyte hypertrophy and apoptosis have been implicated in the loss of contractile function during heart failure (HF). Moreover, patients with HF have been shown to exhibit increased levels of tumor necrosis factor alpha (TNF-alpha) in the myocardium. However, the multiple signal transduction pathways generating from the TNF-alpha receptor in cardiomyocytes and leading preferentially to apoptosis or hypertrophy are still unknown. Here we demonstrate in neonatal rat cardiomyocytes that 1) TNF-alpha induces phosphorylation of AKT, activation of NF-kappaB, and the phosphorylation of JUN kinase; 2) blocking AKT activity prevents NF-kappaB activation, suggesting a role for AKT in regulating NF-kappaB function; 3) AKT and JUN are both critical for the hypertrophic effects of TNF-alpha, since dominant-negative mutants of these genes are capable of inhibiting TNF-alpha-induced ANF-promoter up-regulation and increase in cardiomyocyte cell size, and 4) blocking NF-kappaB, AKT, or JUN alone or in combination does not sensitize cardiomyocytes to the proapoptotic effects of TNF-alpha, in contrast to other cell types, suggesting a cardiac-specific pathway regulating the anti-apoptotic events induced by TNF-alpha. Altogether, the data presented evidence the role of AKT and JUN in TNF-alpha-induced cardiomyocyte hypertrophy and apoptosis.

Animals↗