Members of the mitogen-activated protein kinase (MAPK) cascade such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 are implicated as important regulators of cardiomyocyte hypertrophic growth in culture. However, the role that individual MAPK pathways play in vivo has not been extensively evaluated. Here we generated nine transgenic mouse lines with cardiac-restricted expression of an activated MEK1 cDNA in the heart. MEK1 transgenic mice demonstrated concentric hypertrophy without signs of cardiomyopathy or lethality up to 12 months of age. MEK1 transgenic mice showed a dramatic increase in cardiac function, as measured by echocardiography and isolated working heart preparation, without signs of decompensation over time. MEK1 transgenic mice and MEK1 adenovirus-infected neonatal cardiomyocytes each demonstrated ERK1/2, but not p38 or JNK, activation. MEK1 transgenic mice and MEK1 adenovirus-infected cultured cardiomyocytes were also partially resistant to apoptotic stimuli. The results of the present study indicate that the MEK1-ERK1/2 signaling pathway stimulates a physiologic hypertrophy response associated with augmented cardiac function and partial resistance to apoptotsis.

Rationale: Aberrant expression profiles of circulating microRNAs (miRNAs) have been described in various diseases and provide high sensitivity and specificity. We explored circulating miRNAs as potential biomarkers in patients with heart failure (HF). Objective: The goal of this study was to determine whether miRNAs allow to distinguish clinical HF not only from healthy controls but also from non-HF forms of dyspnea. Methods and Results: A miRNA array was performed on plasma of 12 healthy controls and 12 HF patients. From this array, we selected 16 miRNAs for a second clinical study in 39 healthy controls and in 50 cases with reports of dyspnea, of whom 30 were diagnosed with HF and 20 were diagnosed with dyspnea attributable to non-HF-related causes. This revealed that miR423-5p was specifically enriched in blood of HF cases and receiver-operator-characteristics (ROC) curve analysis showed miR423-5p to be a diagnostic predictor of HF, with an area under the curve of 0.91 (P<0.001). Five other miRNAs were elevated in HF cases but also slightly increased in non-HF dyspnea cases. Conclusion: We identify 6 miRNAs that are elevated in patients with HF, among which miR423-5p is most strongly related to the clinical diagnosis of HF. Recent studies have unveiled powerful and unexpected roles for microRNAs (miRNAs) in cardiovascular diseases, including HF. There are estimated to be more than 1000 different miRNAs, many of which are expressed in a tissue and cell-specific manner. 3 It was discovered only recently that miRNAs are also abundantly present in blood, where they can be detected in plasma, platelets, and erythrocytes, as well as in nucleated blood cells. 4 Aberrant expression profiles of miRNAs have been identified in blood of subjects with sickle cell anemia, prostate cancer, lung cancer and myocardial injury. 4 -6 This led us to hypothesize that miRNA profiling can also be used for diagnostic approaches in HF.Here we explored whether circulating miRNAs can be used as biomarkers in patients with HF. We first performed miRNA arrays on RNA isolated from plasma and selected 16 miRNAs expressed differentially in HF patients. Next, we evaluated these miRNAs in a second group of patients, consisting of 50 cases with reports of dyspnea, of whom 30 were diagnosed with HF (HF cases) and 20 were diagnosed to have dyspnea attributable to non-HF causes (non-HF cases). One circulating miRNA in particular, miR423-5p, was able to distinguish HF cases from non-HF cases.In conclusion, we demonstrate a number of miRNAs as putative biomarkers for HF, in particular miR423-5p. MethodsHuman plasma samples were obtained with informed consent under a general waiver by the Academic Medical Center institutional review board for the proper secondary use of human material. For the dyspnea registry, plasma samples were obtained as part of a multicenter effort involving 3 centers in The Netherlands. Experiments described were performed on samples obtained at the Academic Medical Center. For a detailed description of the dyspnea registry,...