Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

cGMP-dependent protein kinase (PKG) is the major intracellular receptor for cyclic guanosine monophosphate (cGMP). Two forms of PKG, PKG-I and PKG-II, occur in mammalian tissues. PKG may mediate nitric oxide-cGMP-induced vasodilation through decreasing intracellular calcium concentration by the activation of calcium-activated potassium channel on the cell membrane and phosphorylation of phospholamban (PLB) and IP3 receptor-associated PKG-I substrate (IRAG) on the sarcoplasmic reticulum. PKG may also decrease the sensitivity of myosin to calcium by stimulating the activity of myosin light chain phosphatase and by inhibiting Rho kinase activity. PKG plays an important role in regulating the gene expression, phenotype, and proliferation of vascular smooth muscle cells. PKG activation inhibits platelet aggregation and myocardial hypertrophy. Recent studies indicate that the alternations of PKG expression and activity are closely related with the pathogenesis of atherosclerosis, restenosis, hypertension, hyperlipemia as well as nitrate tolerance.
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PMID:[Role of cGMP-dependent protein kinase in the cardiovascular system]. 1640 66

Diabetes mellitus (DM) causes the development of a specific cardiomyopathy that results from the metabolic derangements present in DM and manifests as cardiac contractile dysfunction. Although myocardial dysfunction in Type 1 DM has been associated with defects in the function and regulation of the sarcoplasmic reticulum (SR), very little is known about SR function in Type 2 DM. Accordingly, this study examined whether abnormalities in cardiac contractile performance and SR function occur in the prestage of Type 2 DM (i.e., during insulin resistance). Sucrose feeding was used to induce whole body insulin resistance, whereas cardiac contractile performance was assessed by echocardiography and SR function was measured by SR calcium (Ca(2+)) uptake. Sucrose-fed rats exhibited hyperinsulinemia, hyperglycemia, and hyperlipidemia relative to control rats. Serial echocardiographic assessments in the sucrose-fed rats revealed early abnormalities in diastolic function followed by late systolic dysfunction and concurrent alterations in myocardial structure. The hearts of the 10-wk sucrose-fed rats showed depressed SR function demonstrated by a significant reduction in SR Ca(2+) uptake. The decline in SR Ca(2+) uptake was associated with a significant decrease in the cAMP-dependent protein kinase and Ca(2+)/calmodulin-dependent protein kinase II-mediated phosphorylation of phospholamban. The results show that abnormalities in cardiac contractile performance and SR function occur at an insulin-resistant stage before the manifestation of overt Type 2 DM.
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PMID:Alterations in cardiac contractile performance and sarcoplasmic reticulum function in sucrose-fed rats is associated with insulin resistance. 1697 23

Emerging evidence indicates that leptin may be a potential new target in chronic heart failure (CHF) treatment. We hypothesized that hyperleptinemia may correlate with abnormal expression of SERCA2a, PLB (phospholamban), and the endothelin (ET) pathway in CHF. An activated ET pathway is involved in CHF that is suppressed by CPU86017 (p-chlorobenzyltetrahydroberberine chloride), a complex class III antiarrhythmic agent with an antioxidant effect. Thus, relief of CHF may be mediated by a reversal of abnormalities of the leptin system, the ET-reactive oxygen species (ROS) pathway, SERCA2a, and PLB by CPU86017. CHF was produced by coronary artery ligation for 6 weeks in rats. The rats were divided into 3 groups: sham, CHF untreated, and CHF+CPU86017 (4 mg/kg per day, s.c.). Hemodynamic changes, cardiac morphology, serum biochemistry, messenger ribonucleic acid (mRNA) and protein expression of the leptin pathway, ET pathway, and redox were measured. In CHF rats, hemodynamic abnormalities, cardiac remodeling, and histological changes with features of cardiac failure were associated with hyperlipidemia accompanied by oxidative stress and upregulated OB-Rb, ECE, pp-ET-1, ET(A)R, and ET(B)R mRNA expression in the myocardium. Protein expression of leptin and ET(A)R in the myocardium was markedly increased in CHF rats. An activated leptin pathway was associated with downregulation of SERCA2a and upregulation of PLB in mRNA and protein expression in CHF. CPU86017 downregulated the leptin system and reversed the above changes in the myocardium. An activated leptin pathway correlates with abnormal expression of SERCA2a and PLB and an activated ET-ROS system in the affected myocardium. The multi-ion-channel-blocking and antioxidative effects of CPU86017 downregulate the leptin pathway and ET system, resulting in reversal of the abnormalities of expression of SERCA2a and PLB and cardiac performance in CHF.
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PMID:Upregulation of leptin pathway correlates with abnormal expression of SERCA2a, phospholamban and the endothelin pathway in heart failure and reversal by CPU86017. 1728 47