Heart failure, caused by dilated cardiomyopathy and other cardiac disorders such as hypertension, is a major public health problem with high morbidity and mortality. Corin, a cardiac enzyme that cleaves natriuretic peptides, is a promising biomarker of cardiomyopathy and heart failure—but its functional role in these processes is not understood. We evaluated the potential effects of corin in mice with a well-characterized model of dilated cardiomyopathy. Mice with dilated cardiomyopathy developed heart failure, reduced contractile function, cardiac fibrosis and accelerated mortality in the setting of low corin expression. In wild-type mice, transgenic, cardiac-targeted, over-expression of corin enhanced cyclic guanosine monophosphate and blood pressure responses to pro-atrial natriuretic peptide, but did not affect heart size, contractility, body weights, survival and blood pressure. In mice with dilated cardiomyopathy, corin overexpression significantly reduced the development of myocardial fibrosis (p<0.05). Corin over-expression also enhanced heart contractile function (fractional shortening and ejection fraction (p<0.01) and it significantly reduced heart failure as assessed by lung water (p<0.05) and alveolar congestion (p<0.001). Consistent with these observations, corin over-expression significantly prolonged life in mice with dilated cardiomyopathy (p<0.0001). These results provide the first experimental evidence that corin expression plays a role in cardiomyopathy by modulating myocardial fibrosis, cardiac function, heart failure and survival.
Background— Platelet aggregation plays a critical role in myocardial infarction and stroke; however, the role of platelet secretion in atherosclerotic vascular disease is poorly understood. Therefore, we examined the hypothesis that platelet dense-granule secretion modulates thrombosis, inflammation, and atherosclerotic vascular remodeling after injury. Methods and Results— Functional deletion of the Hermansky-Pudlak syndrome 3 gene (HPS3 −/− ) markedly reduces platelet dense-granule secretion. HPS3 −/− mice have normal platelet counts, platelet morphology, and α-granule number, as well as maximal secretion of the α-granule marker P-selectin; however, their capacity to form platelet-leukocyte aggregates is significantly reduced ( P <0.05). To examine the role of platelet dense-granule secretion in these processes, atherosclerosis-prone mice with combined genetic deficiency of apolipoprotein E and HPS3 (ApoE −/− , HPS3 −/− ) were compared with congenic, atherosclerosis-prone mice with normal platelet secretion (ApoE −/− , HPS3 +/+ ). After 16 to 18 weeks on a high-fat diet, both groups of mice had similar fasting cholesterol levels and body weight. Carotid arteries of ApoE −/− , HPS3 +/+ mice thrombosed rapidly after FeCl 3 injury, but ApoE −/− , HPS3 −/− mice were completely resistant to thrombotic arterial occlusion ( P <0.01). Three weeks after injury, neointimal hyperplasia (from α-smooth muscle actin–positive cells) was significantly less ( P <0.001) in arteries from ApoE −/− , HPS3 −/− mice. In ApoE −/− , HPS3 −/− mice, there were also pronounced reductions in arterial inflammation, as indicated by a 74% decrease in CD45-positive leukocytes ( P <0.01) and a 73% decrease in Mac-3–positive macrophages ( P <0.05). Conclusions— In atherosclerotic mice, reduced platelet dense-granule secretion is associated with marked protection against the development of arterial thrombosis, inflammation, and neointimal hyperplasia after vascular injury.
Signaling through cAMP plays an important role in heart failure. Phosphorylation of cAMP response element binding protein (CREB) at serine-133 regulates gene expression in the heart. We examined the functional significance of CREB-S133 phosphorylation by comparing transgenic models in which a phosphorylation resistant CREB-S133A mutant containing either an intact or a mutated leucine zipper domain (CREB-S133A-LZ) was expressed in the heart. In vitro, CREB-S133A retained the ability to interact with wild-type CREB, whereas CREB-S133A-LZ did not. In vivo, CREB-S133A and CREB-S133A-LZ were expressed at comparable levels in the heart; however, CREB-S133A markedly suppressed the phosphorylation of endogenous CREB, whereas CREB-S133A-LZ had no effect. The one-year survival of mice from two CREB-S133A-LZ transgenic lines was equivalent to nontransgenic littermate control mice (NTG), whereas transgenic CREB-S133A mice died with heart failure at a median 30 wk of age (P < 0.0001). CREB-S133A mice had an altered gene expression characteristic of the failing heart, whereas CREB-S133A-LZ mice did not. Left ventricular contractile function was substantially reduced in CREB-S133A mice versus NTG mice and only modestly reduced in CREB-S133A-LZ mice (P < 0.02). When considered in light of other studies, these findings indicate that overexpression of the CREB leucine zipper is required for both inhibition of endogenous CREB phosphorylation and cardiomyopathy in this murine model of heart failure. Keywordsadenosine; 3′,5′-cyclic; monophosphate; responsive; element; binding; protein Signaling through cAMP plays an important role in the pathogenesis of human heart failure (30). One target of cAMP signaling in cardiac myocytes is transcriptional regulation mediated through the 43-kDa basic leucine zipper transcription factor cAMP responsive element (CRE) binding protein (CREB). Members of the CREB/CRE modulator (CREM)/ activating transcription factor (ATF) family of transcription factors have important roles in © 2007 the American Physiological Society Address for reprint requests and other correspondence: G. S. Huggins, MCRI Ctr. for Translational Genomics, Tufts-New England Medical Ctr., 750 Washington St., Boston, MA 02111 (ghuggins@tufts-nemc.org). (6,16,26,29). Myocardial target genes of CREB relevant to the pathogenesis of heart failure include Bcl2 (14, 32), inducible cAMP early repressor (3), and cardiotrophin-1 (9, 14). NIH Public AccessThe CREB/CREM/ATF family members contain a kinase-inducible transcriptional activation domain (10). Within this domain, CREB serine-133 is phosphorylated in cardiomyocytes following adrenergic stimulation (23) by cAMP-dependent activation of PKA (18) and by other kinase pathways relevant to cardiomyocyte survival and contractility, including Akt (4) and p38 mitogen-and stress-activated protein kinase-1 (18). cAMPstimulated CREB serine-133 phosphorylation leads to its association with CREB binding protein (CBP) and p300 coactivator protein binding (20), activating gene expression sel...
Summary Background: Given the worldwide epidemic of cardiovascular diseases, a more effective means of dissolving thrombi that cause heart attacks, could markedly reduce death, disability and healthcare costs. Plasminogen activators (PAs) such as streptokinase (SK) and tissue plasminogen activator (TPA) are currently used to dissolve fibrin thrombi. SK is cheaper and more widely available, but it appears less effective because it lacks TPA’s fibrin-targeted properties that focus plasminogen activation on the fibrin surface. Objective: We examined whether re-programming SK’s mechanism of action would create PAs with greater fibrin-targeting and potency than TPA. Methods and Results: When fibrinogen consumption was measured in human plasma, reprogrammed molecules SKΔ1 and SKΔ59 were 5-fold and > 119-fold more fibrin-dependent than SK (P < 0.0001), and 2-fold and > 50-fold more fibrin-dependent than TPA (P < 0.001). The marked fibrin-targeting of SKΔ59 was due to the fact that: (i) it did not generate plasmin in plasma, (ii) it was rapidly inhibited by α2-antiplasmin, and (iii) it only processed fibrin-bound plasminogen. To assess the fibrin-targeting and therapeutic potential of these PAs in vivo, a novel ‘humanized’ fibrinolysis model was created by reconstituting plasminogen-deficient mice with human plasminogen. When compared with TPA, SKΔ1 and SKΔ59 were 4-fold (P < 0.0001) and 2-fold (P < 0.003) more potent at dissolving blood clots in vivo, respectively, on a mass-dose basis and 2–3 logs more potent than TPA (P < 0.0001) when doses were calibrated by standard activity assays. Conclusion: These experiments suggest that reprogramming SK’s mechanism of action markedly enhances fibrin-targeting and creates, in comparison with TPA, activators with greater fibrinolytic potency.
Houng AK, McNamee RA, Kerner A, Sharma P, Mohamad A, Tronolone J, Reed GL. Atrial natriuretic peptide increases inflammation, infarct size, and mortality after experimental coronary occlusion.
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