atrial-natriuretic-factor and olmesartan

The gene ankyrin repeat domain 1 (Ankrd1) is an enigmatic gene and may exert pleiotropic function dependent on its expression level, subcellular localization and even types of pathological stress, but it remains unclear how these factors influence the fate of cardiomyocytes. Here we attempted to investigate the role of CARP on cardiomyocyte hypertrophy. In neonatal rat ventricular cardiomyocytes (NRVCs), angiotensin II (Ang II) increased the expression of both calpain 1 and CARP, and also induced cytosolic translocation of CARP, which was abrogated by a calpain inhibitor. In the presence of Ang-II in NRVCs, infection with a recombinant adenovirus containing rat Ankrd1 cDNA (Ad-Ankrd1) enhanced myocyte hypertrophy, the upregulation of atrial natriuretic peptide and β-myosin heavy chain genes and calcineurin proteins as well as nuclear translocation of nuclear factor of activated T cells. Cyclosporin A attenuated Ad-Ankrd1-enhanced cardiomyocyte hypertrophy. Intra-myocardial injection of Ad-Ankrd1 in mice with transverse aortic constriction (TAC) markedly increased the cytosolic CARP level, the heart weight/body weight ratio, while short hairpin RNA targeting Ankrd1 inhibited TAC-induced hypertrophy. The expression of calcineurin was also significantly increased in Ad-Ankrd1-infected TAC mice. Olmesartan (an Ang II receptor antagonist) prevented the upregulation of CARP in both Ang II-stimulated NRVCs and hearts with pressure overload. These findings indicate that overexpression of Ankrd1 exacerbates pathological cardiac remodeling through the enhancement of cytosolic translocation of CARP and upregulation of calcineurin.

Topics: Adenoviridae; Angiotensin II; Animals; Animals, Newborn; Aorta; Atrial Natriuretic Factor; Calcineurin; Calpain; Cardiomegaly; Constriction, Pathologic; Cyclosporine; Gene Expression Regulation; Genetic Vectors; Glycoproteins; Imidazoles; Mice; Muscle Proteins; Myocytes, Cardiac; Myosin Heavy Chains; Nuclear Proteins; Primary Cell Culture; Protein Transport; Rats; Repressor Proteins; RNA, Small Interfering; Signal Transduction; Tetrazoles

Kruppel-like factor 4 (KLF4) plays an important role in vascular diseases, including atherosclerosis and vascular injury. Although KLF4 is expressed in the heart in addition to vascular cells, the role of KLF4 in cardiac disease has not been fully determined. The goals of this study were to investigate the role of KLF4 in cardiac hypertrophy and to determine the underlying mechanisms. Cardiomyocyte-specific Klf4 knockout (CM Klf4 KO) mice were generated by the Cre/LoxP technique. Cardiac hypertrophy was induced by chronic infusion of the β-adrenoreceptor agonist isoproterenol (ISO). Results showed that ISO-induced cardiac hypertrophy was enhanced in CM Klf4 KO mice compared with control mice. Accelerated cardiac hypertrophy in CM Klf4 KO mice was accompanied by the augmented cellular enlargement of cardiomyocytes as well as the exaggerated expression of fetal cardiac genes, including atrial natriuretic factor (Nppa). Additionally, induction of myocardin, a transcriptional cofactor regulating fetal cardiac genes, was enhanced in CM Klf4 KO mice. Interestingly, KLF4 regulated Nppa expression by modulating the expression and activity of myocardin, providing a mechanical basis for accelerated cardiac hypertrophy in CM Klf4 KO mice. Moreover, we showed that KLF4 mediated the antihypertrophic effect of trichostatin A, a histone deacetylase inhibitor, because ISO-induced cardiac hypertrophy in CM Klf4 KO mice was attenuated by olmesartan, an angiotensin II type 1 antagonist, but not by trichostatin A. These results provide novel evidence that KLF4 is a regulator of cardiac hypertrophy by modulating the expression and the activity of myocardin.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Cardiomegaly; Cell Line; Gene Expression; Gene Expression Regulation; Histone Deacetylase Inhibitors; Hydroxamic Acids; Imidazoles; Isoproterenol; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Myocytes, Cardiac; Natriuretic Peptide, C-Type; Nuclear Proteins; Protein Precursors; Tetrazoles; Trans-Activators

Transgenic mice with transient cardiac expression of constitutively active Galpha q (Gαq-TG) exhibt progressive heart failure and ventricular arrhythmias after the initiating stimulus of transfected constitutively active Gαq becomes undetectable. However, the mechanisms are still unknown. We examined the effects of chronic administration of olmesartan on heart failure and ventricular arrhythmia in Gαq-TG mice.. Olmesartan (1 mg/kg/day) or vehicle was chronically administered to Gαq-TG from 6 to 32 weeks of age, and all experiments were performed in mice at the age of 32 weeks. Chronic olmesartan administration prevented the severe reduction of left ventricular fractional shortening, and inhibited ventricular interstitial fibrosis and ventricular myocyte hypertrophy in Gαq-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 9 of 10 vehicle-treated Gαq-TG but in none of 10 olmesartan-treated Gαq-TG. The collected QT interval and monophasic action potential duration in the left ventricle were significantly shorter in olmesartan-treated Gαq-TG than in vehicle-treated Gαq-TG. CTGF, collagen type 1, ANP, BNP, and β-MHC gene expression was increased and olmesartan significantly decreased the expression of these genes in Gαq-TG mouse ventricles. The expression of canonical transient receptor potential (TRPC) 3 and 6 channel and angiotensin converting enzyme (ACE) proteins but not angiotensin II type 1 (AT1) receptor was increased in Gαq-TG ventricles compared with NTG mouse ventricles. Olmesartan significantly decreased TRPC6 and tended to decrease ACE expressions in Gαq-TG. Moreover, it increased AT1 receptor in Gαq-TG.. These findings suggest that angiotensin II type 1 receptor activation plays an important role in the development of heart failure and ventricular arrhythmia in Gαq-TG mouse model of heart failure.

Topics: Adaptor Proteins, Signal Transducing; Animals; Atrial Natriuretic Factor; Collagen Type I; Disease Models, Animal; Gene Expression Regulation; GTP-Binding Protein alpha Subunits, Gq-G11; Heart Failure; Imidazoles; Mice; Mice, Transgenic; Myosin Heavy Chains; Tetrazoles; Ventricular Premature Complexes

Angiotensin II (AngII) type 1-receptor blockers (ARBs) have been effectively used not only in the treatment of hypertension but also in cardiac protection. However, whether and why there are differences in these effects still remain unclear. Here we compared the effects of five commonly used ARBs (Candesartan, Olmesartan, Losartan, Telmisartan and Valsartan) on pressure overload-induced cardiac hypertrophy in mice model. Pressure overload was produced by constriction of the transverse aorta (TAC) for 2 weeks, which induced a significant elevation of blood pressure; ARBs or saline was administered through a stomach tube; Cardiac hypertrophy was evaluated by transthoracic echocardiography, cardiac histology and specific gene expression analyses. Although all the five ARBs, which did not repress the elevation of left ventricular pressure after TAC, attenuated the development of cardiac hypertrophy in the wild-type mice, the degrees of regression by Candesartan, Olmesartan and Losartan tended to be larger than those by Telmisartan and Valsartan. Furthermore, in angiotensinogen-knockout mice lacking endogenous AngII, TAC-induced cardiac hypertrophy was regressed by Candesartan, Olmesartan and Losartan but not by Telmisartan and Valsartan administration. Our data suggest that Candesartan, Olmesartan and Losartan can effectively inhibit pressure overload-induced cardiac hypertrophy even in the absence of AngII, whereas Telmisartan and Valsartan could exert the inhibitory effects only in the presence of AngII.

Topics: Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Benzimidazoles; Benzoates; Biphenyl Compounds; Blood Pressure; Cardiomegaly; Echocardiography; Gene Expression; Hemodynamics; Imidazoles; Losartan; Male; Mice; Myocardium; Reverse Transcriptase Polymerase Chain Reaction; Telmisartan; Tetrazoles; Treatment Outcome; Valine; Valsartan

The cardiac natriuretic peptides atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are discoordinately regulated in myocardial inflammation associated with acute allograft rejection in humans and during in vitro exposure of cardiocyte cultures to some proinflammatory cytokines. We used experimental autoimmune myocarditis (EAM) to determine whether the discoordinate regulation of ANF and BNP was specific to the situations above or was generally associated with other types of myocardial inflammation. The dependency of this process to angiotensin signaling was also determined, given that previous work demonstrated beneficial effects of the angiotensin receptor blocker olmesartan in myocarditis. Histopathological changes, plasma and cardiac ANF, BNP, and selected cytokines gene expression as well as plasma cytokine levels using a cytokine array were determined in EAM, angiotensin receptor blocker-treated, and control rats. It was found that EAM specifically increases BNP but not ANF circulating levels, thus mimicking the findings in acute cardiac allograft rejection and the effect of some proinflammatory cytokines on cardiocyte cultures in vitro. Plasma cytokine array and real-time PCR revealed that lipopolysaccharide-induced CXC chemokine, monocyte chemotactic protein-1, and tissue inhibitor of metalloproteinase-1 were increased in plasma and in the myocardium of EAM rats. Olmesartan treatment reversed virtually all neuroendocrine and histopathological cardiac changes induced by EAM, thus providing a mechanistic insight into this phenomenon. It is concluded that the inflammatory process contributes specific cytokines, leading to the disregulation of cardiac ANF and BNP production observed during myocardial inflammation, and that this process is angiotensin receptor 1 dependent.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Atrial Natriuretic Factor; Blood Pressure; Cytokines; Disease Models, Animal; Imidazoles; Mycobacterium tuberculosis; Myocarditis; Myocardium; Natriuretic Peptide, Brain; Polymerase Chain Reaction; Protein Array Analysis; Rats; Rats, Inbred Lew; Receptor, Angiotensin, Type 1; RNA, Messenger; Tetrazoles; Up-Regulation