Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Class I phosphoinositide 3-kinases (PI3Ks) are enzymes with both protein and lipid kinase activities that have ubiquitous cellular functions. In the heart, subclass IA PI3Ks, PI3K-alpha and beta, regulate cell growth, apoptosis, cell division and cell size, whereas PI3Kgamma, the only member of subclass IB, has been shown to regulate myocardial contractility. Loss of p110gamma, the catalytic subunit of PI3Kgamma, enhances cardiac excitation-contraction coupling by modulating cyclic adenosine monophosphate (cAMP) levels in subcellular domains containing the sarcoplasmic reticulum (SR) leading to increased cAMP-mediated phosphorylation of phospholamban. The ability of p110gamma to modulate cAMP is likely mediated by the protein-protein interactions with the cAMP-degrading enzymes, phosphodiesterases, independent of its lipid kinase activity. PI3Kgamma also plays a key role in modulating the cAMP response and desensitization of beta-adrenergic receptors. Loss of p110gamma gamma leads to acute decompensation and rapid progression into heart failure in response to pathological biomechanical stress while lipid kinase-dead mutants were relatively resistant suggesting that elevated intracellular cAMP (and its secondary effects) is an important predisposing factor for heart failure. The commercial availability of specific PI3Kgamma inhibitors may be used as therapeutic agents in inflammatory and cardiovascular diseases. In this review article, we discuss the key role of PI3Kgamma gamma in regulating cAMP, Ca(2+) cycling, beta-adrenergic signaling and myocardial structure and function in heart disease.
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PMID:Role of PI3 kinase gamma in excitation-contraction coupling and heart disease. 1822 Jul 29

Tumor necrosis factor (TNF) is an inflammatory cytokine that is upregulated in a number of cardiomyopathies. Adverse cardiac remodeling and dilation result from degradation of the extracellular matrix by matrix metalloproteinases (MMPs). We investigated whether TNF can directly trigger expression and activation of MMPs in cardiac cells. We compared MMP expression profile and activities between primary cultures of mouse neonatal cardiomyocytes and cardiofibroblasts and in cellular and extracellular compartments. In response to recombinant TNF (rTNF, 20 ng/ml), cardiomyocytes exhibited faster and more pronounced superoxide production compared with cardiofibroblasts, concomitant with increased expression of several MMPs. MMP9 levels increased more rapidly and about twofold more in cardiomyocytes than in cardiofibroblasts. TNF did not induce MMP2 expression. Expression of collagenases (MMP8, MMP12, MMP13, and MMP14) increased significantly, while total collagenase activity increased to a greater degree in conditioned medium of cardiomyocytes than in cardiofibroblasts. rTNF-mediated MMP expression and activation were dependent on superoxide production and were blocked by apocynin, an NADPH oxidase inhibitor. We identified phosphatidylinositol 3-kinase (PI3K)gamma as a key factor in TNF-mediated events since TNF-induced superoxide production, MMP expression, and activity were significantly suppressed in cardiomyocytes and cardiofibroblasts deficient in PI3Kgamma. We further demonstrated that the TNF-superoxide-MMP axis of events is in fact activated in heart disease in vivo. Wild-type and TNF(-/-) mice subjected to cardiac pressure overload revealed that TNF deficiency resulted in reduced superoxide levels, collagenase activities, PI3K activity, and fibrosis leading to attenuated cardiac dilation and dysfunction. Our study demonstrates that TNF triggers expression and activation of MMPs faster and stronger in cardiomyocytes than in cardiofibroblasts in a superoxide-dependent manner and via activation of PI3Kgamma, thereby contributing to adverse myocardial remodeling in disease.
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PMID:Tumor necrosis factor induces matrix metalloproteinases in cardiomyocytes and cardiofibroblasts differentially via superoxide production in a PI3Kgamma-dependent manner. 2000 53

Although angiotensin II (Ang II) plays an important role in heart disease associated with pump dysfunction, its direct effects on cardiac pump function remain controversial. We found that after Ang II infusion, the developed pressure and +dP/dt(max) in isolated Langendorff-perfused mouse hearts showed a complex temporal response, with a rapid transient decrease followed by an increase above baseline. Similar time-dependent changes in cell shortening and L-type Ca(2+) currents were observed in isolated ventricular myocytes. Previous studies have established that Ang II signaling involves phosphoinositide 3-kinases (PI3K). Dominant-negative inhibition of PI3Kalpha in the myocardium selectively eliminated the rapid negative inotropic action of Ang II (inhibited by approximately 90%), whereas the loss of PI3Kgamma had no effect on the response to Ang II. Consistent with a link between PI3Kalpha and protein kinase C (PKC), PKC inhibition (with GF 109203X) reduced the negative inotropic effects of Ang II by approximately 50%. Although PI3Kalpha and PKC activities are associated with glycogen synthase kinase-3beta and NADPH oxidase, genetic ablation of either glycogen synthase kinase-3beta or p47(phox) (an essential subunit of NOX2-NADPH oxidase) had no effect on the inotropic actions of Ang II. Our results establish that Ang II has complex temporal effects on contractility and L-type Ca(2+) channels in normal mouse myocardium, with the negative inotropic effects requiring PI3Kalpha and PKC activities.
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PMID:Role of phosphoinositide 3-kinase {alpha}, protein kinase C, and L-type Ca2+ channels in mediating the complex actions of angiotensin II on mouse cardiac contractility. 2069 91