The orphan receptor APJ and its recently identified endogenous ligand, apelin, exhibit high levels of mRNA expression in the heart. However, the functional importance of apelin in the cardiovascular system is not known. In isolated perfused rat hearts, infusion of apelin (0.01 to 10 nmol/L) induced a dose-dependent positive inotropic effect (EC50: 33.1+/-1.5 pmol/L). Moreover, preload-induced increase in dP/dt(max) was significantly augmented (P<0.05) in the presence of apelin. Inhibition of phospholipase C (PLC) with U-73122 and suppression of protein kinase C (PKC) with staurosporine and GF-109203X markedly attenuated the apelin-induced inotropic effect (P<0.001). In addition, zoniporide, a selective inhibitor of Na+-H+ exchange (NHE) isoform-1, and KB-R7943, a potent inhibitor of the reverse mode Na+-Ca2+ exchange (NCX), significantly suppressed the response to apelin (P<0.001). Perforated patch-clamp recordings showed that apelin did not modulate L-type Ca2+ current or voltage-activated K+ currents in isolated adult rat ventricular myocytes. Apelin mRNA was markedly downregulated in cultured neonatal rat ventricular myocytes subjected to mechanical stretch and in vivo in two models of chronic ventricular pressure overload. The present study provides the first evidence for the physiological significance of apelin in the heart. Our results show that apelin is one of the most potent endogenous positive inotropic substances yet identified and that the inotropic response to apelin may involve activation of PLC, PKC, and sarcolemmal NHE and NCX.

BackgroundDiabetes mellitus is linked to premature mortality of virtually all causes. Furin is a proprotein convertase broadly involved in the maintenance of cellular homeostasis; however, little is known about its role in the development of diabetes mellitus and risk of premature mortality.ObjectivesTo test if fasting plasma concentration of furin is associated with the development of diabetes mellitus and mortality.MethodsOvernight fasted plasma furin levels were measured at baseline examination in 4678 individuals from the population‐based prospective Malmö Diet and Cancer Study. We studied the relation of plasma furin levels with metabolic and hemodynamic traits. We used multivariable Cox proportional hazards models to investigate the association between baseline plasma furin levels and incidence of diabetes mellitus and mortality during 21.3–21.7 years follow‐up.ResultsAn association was observed between quartiles of furin concentration at baseline and body mass index, blood pressure and plasma concentration of glucose, insulin, LDL and HDL cholesterol (|0.11| ≤ β ≤ |0.31|, P < 0.001). Plasma furin (hazard ratio [HR] per one standard deviation increment of furin) was predictive of future diabetes mellitus (727 events; HR = 1.24, CI = 1.14–1.36, P < 0.001) after adjustment for age, sex, body mass index, systolic and diastolic blood pressure, use of antihypertensive treatment, alcohol intake and fasting plasma level of glucose, insulin and lipoproteins cholesterol. Furin was also independently related to the risk of all‐cause mortality (1229 events; HR = 1.12, CI = 1.05–1.19, P = 0.001) after full multivariable adjustment.ConclusionIndividuals with high plasma furin concentration have a pronounced dysmetabolic phenotype and elevated risk of diabetes mellitus and premature mortality.

Mechanical forces are able to activate hypertrophic growth of cardiomyocytes in the overloaded myocardium. However, the transcriptional profiles triggered by mechanical stretch in cardiac myocytes are not fully understood. Here, we performed the first genome-wide time series study of gene expression changes in stretched cultured neonatal rat ventricular myocytes (NRVM)s, resulting in 205, 579, 737, 621, and 1542 differentially expressed (>2-fold, P < 0.05) genes in response to 1, 4, 12, 24, and 48 hours of cyclic mechanical stretch. We used Ingenuity Pathway Analysis to predict functional pathways and upstream regulators of differentially expressed genes in order to identify regulatory networks that may lead to mechanical stretch induced hypertrophic growth of cardiomyocytes. We also performed micro (miRNA) expression profiling of stretched NRVMs, and identified that a total of 8 and 87 miRNAs were significantly (P < 0.05) altered by 1–12 and 24–48 hours of mechanical stretch, respectively. Finally, through integration of miRNA and mRNA data, we predicted the miRNAs that regulate mRNAs potentially leading to the hypertrophic growth induced by mechanical stretch. These analyses predicted nuclear factor-like 2 (Nrf2) and interferon regulatory transcription factors as well as the let-7 family of miRNAs as playing roles in the regulation of stretch-regulated genes in cardiomyocytes.

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Abstract-Mitogen-activated protein kinases (MAPKs) regulate cardiomyocyte growth and apoptosis in response to extracellular stimulation, but the downstream effectors that mediate their pathophysiological effects remain poorly understood. We determined the targets and role of p38 MAPK in the heart in vivo by using local adenovirus-mediated gene transfer of constitutively active upstream kinase mitogen-activated protein kinase kinase 3b (MKK3bE) and wild-type p38␣ in rats. DNA microarray analysis of animals with cardiac-specific overexpression of p38 MAPK revealed that 264 genes were upregulated more than 2-fold including multiple genes controlling cell division, cell signaling, inflammation, adhesion, and transcription. A large number of previously unknown p38 target genes were found. Using gel mobility-shift assays we identified several cardiac transcription factors that were directly activated by p38 MAPK. Finally, we determined the functional significance of the altered cardiac gene-expression profile by histological analysis and echocardiographic measurements, which indicated that p38 MAPK overexpression-induced gene expression results in myocardial cell proliferation, inflammation, and fibrosis. In conclusion, we defined the novel target genes and transcription factors as well as the functional effects of p38 MAPK in the heart. Expression profiling of p38 MAPK overexpression identified cell cycle regulatory and inflammatory genes critical for pathological processes in the adult heart. (Circ Res. 2006;99:485-493.)

By synthesizing and secreting prohypertrophic cytokines and profibrotic growth factors, cardiac mast cells participate in the induction of cardiac hypertrophy and cardiac fibrosis, which are the key steps in the transition to heart failure.

Rationale:The extracellular matrix (ECM) is a major determinant of the structural integrity and functional properties of the myocardium in common pathological conditions, and changes in vasculature contribute to cardiac dysfunction. Collagen (Col) XV is preferentially expressed in the ECM of cardiac muscle and microvessels.Objective: We aimed to characterize the ECM, cardiovascular function and responses to elevated cardiovascular load in mice lacking Col XV (Col15a1 ؊/؊ ) to define its functional role in the vasculature and in age-and hypertension-associated myocardial remodeling. Methods and Results:Cardiac structure and vasculature were analyzed by light and electron microscopy.Cardiac function, intraarterial blood pressure, microhemodynamics, and gene expression profiles were studied using echocardiography, telemetry, intravital microscopy, and PCR, respectively. Experimental hypertension was induced with angiotensin II or with a nitric oxide synthesis inhibitor. Under basal conditions, lack of Col XV resulted in increased permeability and impaired microvascular hemodynamics, distinct early-onset and age-dependent defects in heart structure and function, a poorly organized fibrillar collagen matrix with marked interstitial deposition of nonfibrillar protein aggregates, increased tissue stiffness, and irregularly organized cardiomyocytes. In response to experimental hypertension, Col15a1 gene expression was increased in the left ventricle of wild-type mice, and mRNA expression of natriuretic peptides (ANP and BNP) and ECM modeling were abnormal in Col15a1 ؊/؊ mice. Key Words: cardiomyopathy Ⅲ collagen Ⅲ extracellular matrix Ⅲ hypertension Ⅲ microcirculation T he extracellular matrix (ECM) has an important role in cardiac remodeling, defined by the adaptive changes in left ventricular structure, geometry, and function that follow cardiovascular stress in hypertensive heart disease, cardiomyopathies, or myocardial infarction and also as a function of age. 1 Degradation of myocardial collagens results in decreased ventricular stiffness and dilatation, whereas an increase in the total interstitial collagen content and crosslinking results in a stiffer myocardium and ventricular diastolic dysfunction. 2 Cardiomyopathy may result from a variety of acquired or genetic factors. In the absence of coronary artery disease, a significant proportion of cardiomyopathies are attributable to a genetic cause, eg, hereditary forms are present in approximately 30% to 50% of patients experiencing dilative cardiomyopathy (DCM), and mutations in more than 30 genes have been linked to this disease. 3 Many defects in cytoskeletal and sarcomeric proteins involved in cardiomyocyte contraction and force production have been associated with familial DCM, but most of the genetic defects and pathophysiological mechanisms have still not been identified. 4 Recent studies using genetically modified mice suggest that altered cell-ECM interactions and cell-cell adhesion via the intercalated discs may be involved in DCM pathogenesis. [5][6]...

We conducted a randomized, open, placebo-controlled crossover trial to investigate the effects of the pregnane X receptor (PXR) agonist rifampin on an oral glucose tolerance test (OGTT) in 12 healthy volunteers. The subjects were administered 600 mg rifampin or placebo once daily for 7 days, and OGTT was performed on the eighth day. The mean incremental glucose and insulin areas under the plasma concentration-time curves (AUC(incr)) increased by 192% (P = 0.008) and 45% (P = 0.031), respectively. The fasting glucose, insulin, and C-peptide, and the homeostasis model assessment for insulin resistance, were not affected. The glucose AUC(incr) during OGTT was significantly increased in rats after 4-day treatment with pregnenolone 16α-carbonitrile (PCN), an agonist of the rat PXR. The hepatic level of glucose transporter 2 (Glut2) mRNA was downregulated by PCN. In conclusion, both human and rat PXR agonists elicited postprandial hyperglycemia, suggesting a detrimental role of PXR activation on glucose tolerance.