Sampsa Pikkarainen - Academia.edu (original) (raw)

Papers by Sampsa Pikkarainen

Scandinavian Journal of Gastroenterology, Jan 12, 2024

Cardiovascular Research, Aug 1, 2004

During the past decade, emerging evidence has accumulated of different nuclear transcription fact... more During the past decade, emerging evidence has accumulated of different nuclear transcription factors in regulation of cardiac development and growth as well as in cardiac hypertrophy and heart failure. GATA-4,-5 and-6 are zinc finger transcription factors that are expressed in the developing heart and GATA-4 and-6 continue expression in the adult cardiac myocytes. GATA-4 and-6 regulate expression of several cardiac-specific genes, and during murine embryonic development, GATA-4 is essential for proper cardiac morphogenesis. In support of this, mutations of gene for GATA-4 or for its cofactors have been associated with human congenital heart disease. Pressure overload of the heart in vivo as well as hypertrophic stimulation of cardiac myocytes in vitro provide adequate stimulus for activation of GATA-4. Activity of GATA-4 transcription factor is subject to regulation at the level of gene expression and through post-translational modifications of GATA-4 protein. A number of genes induced during cardiac hypertrophy possess functional GATA sites in their promoter region and cardiac-specific overexpression of GATA-4 or-6 leads to cardiac hypertrophy. In addition, a pattern of interactions between GATA-4 and its numerous cofactors have been identified, showing an increasing complexity in regulatory mechanisms. The present review discusses current evidence of the role and regulation of GATA transcription factors in the heart, with an emphasis in the GATA-4 and development of cardiac hypertrophy.

Blood Pressure, 2009

Matrix Gla protein (MGP) expression is increased in cardiac hypertrophy, but the precise mechanis... more Matrix Gla protein (MGP) expression is increased in cardiac hypertrophy, but the precise mechanisms regulating its expression are unknown. Here we characterized the effect of pressure overload and myocardial infarction in vivo as well as mechanical stretch and hypertrophic agonists in vitro on MGP expression. When angiotensin II (Ang II) was administered by osmotic minipumps, left ventricular (LV) MGP mRNA levels increased significantly from 6 h to 2 weeks, whereas intravenous arginine(8)-vasopressin increased LV MGP mRNA levels within 4 h. During post-infarction remodeling process, MGP mRNA levels were elevated at 24 h (1.3-fold, p&amp;amp;amp;amp;amp;amp;amp;lt;0.05) and the maximal increase was observed at 4 weeks (2.8-fold, p&amp;amp;amp;amp;amp;amp;amp;lt;0.01). Ang II increased MGP mRNA levels 20% (p&amp;amp;amp;amp;amp;amp;amp;lt;0.05) in neonatal rat cardiac myocytes and 40% (p&amp;amp;amp;amp;amp;amp;amp;lt;0.05) in cardiac fibroblasts, whereas endothelin-1 decreased MGP mRNA levels 30% (p&amp;amp;amp;amp;amp;amp;amp;lt;0.01) in myocytes and had no effect in fibroblasts. Cyclic mechanical stretch resulted in reduction of MGP gene expression in both cardiac myocytes and fibroblasts. These results demonstrate that MGP is rapidly upregulated in response to cardiac overload well before the development of LV hypertrophy and post-infarction remodeling process. Our results also suggest that Ang II may be involved in mediating load-induced activation of MGP expression.

British Journal of Pharmacology, Jan 8, 2010

Background and purpose: The mixed-lineage kinases (MLKs) act upstream of mitogen-activated protei... more Background and purpose: The mixed-lineage kinases (MLKs) act upstream of mitogen-activated protein kinases, but their role in cardiac biology and pathology is largely unknown. Experimental approach: We investigated the effect of a MLK1-3 inhibitor CEP-11004 on G protein-coupled receptor agonist-induced stress response in neonatal rat cardiac myocytes in culture. Key results: CEP-11004 administration dose-dependently attenuated phenylephrine and endothelin-1 (ET-1)-induced c-Jun N-terminal kinase activation. MLK inhibition also reduced ET-1-and phenylephrine-induced phosphorylation of p38 mitogenactivated protein kinase. In contrast, phenylephrine-induced extracellular signal-regulated kinase phosphorylation was further up-regulated by CEP-11004. ET-1 increased activator protein-1 binding activity 3.5-fold and GATA-binding protein 4 (GATA-4) binding activity 1.8-fold, both of which were attenuated with CEP-11004 administration by 59% and 63% respectively. Phenylephrine induced activator protein-1 binding activity by 2.6-fold, which was decreased by 81% with CEP-11004 administration. Phenylephrine also induced a 3.7-fold increase in the transcriptional activity of B-type natriuretic peptide (BNP), which was attenuated by 41% with CEP-11004 administration. In agreement, MLK inhibition also reduced hypertrophic agonist-induced secretion of immunoreactive atrial natriuretic peptide and BNP. Conclusions and implications: These results showed that inhibition of the MLK1-3 signalling pathway was sufficient for suppressing the activity of key nuclear effectors (GATA-4 and activator protein-1 transcription factors) in cardiac hypertrophy, and attenuated the agonist-induced atrial natriuretic peptide secretion and activation of BNP gene transcription.

Journal of Biological Chemistry, Feb 1, 2003

Terminally differentiated cardiac myocytes adapt to mechanical and neurohumoral stress via morpho... more Terminally differentiated cardiac myocytes adapt to mechanical and neurohumoral stress via morphological changes of individual cells accompanied by reactivation of fetal pattern of gene expression. Endothelin-1, a powerful paracrine mediator of myocyte growth, induces similar changes in cultured cardiac myocytes as those seen in hypertrophied heart in vivo. By using rat B-type natriuretic peptide promoter, we identified a novel ETS binding sequence, on which nuclear protein binding is activated in endothelin-1-treated cultured cardiac myocytes. This sequence binds ETS-like gene-1 transcription factor and mediates endothelin-1-specific activation of transcription, but not responses to increased calcium signaling via L-type calcium channels, angiotensin II treatment, or mechanical stretch of myocytes. Interestingly, endothelin-1 activated signaling converges via p38 mitogen-activated protein kinase-dependent mechanism on ETS binding site, whereas this element inhibits extracellular signal-regulated kinase activated transcription. In conclusion, given the fundamental role of the interaction of mitogen-activated protein kinases and ETS factors in regulation of eukaryotic cell differentiation, growth, and oncogenesis, these results provide the unique evidence of a endothelin-1-and mitogenactivated protein kinase-regulated ETS factor pathway for cardiac myocytes.

Journal of Biological Chemistry, Apr 1, 2002

Springer eBooks, Dec 20, 2007

ABSTRACT Cardiac overload initiates a process, which aims to maintain and adapt cardiovascular sy... more ABSTRACT Cardiac overload initiates a process, which aims to maintain and adapt cardiovascular system to altered hemodynamics. In adults, myocardial mass increases mainly due to enlargement of individual myocytes (for reviews, see refs. 1,2). Cardiac pressure overload in conditions such as aortic stenosis or hypertension, results in parallel addition of sarcomeres and increases width of myocytes, which in turn, augment left ventricular wall thickness.2 However, when mechanical and neurohumoral stress are sustained, the adaptive mechanisms eventually fail and further myocardial remodelling leads to ventricular dilation and impairment of cardiac contractile function. Cardiac output reduces until being inadequate to maintain efficient blood circulation of the whole organism and the syndrome of congestive heart failure occurs.2,3 At the cellular level, the cardiac growth and failure is due to a complex pattern of signaling mechanisms and molecules. In 1980s, identification of genes associated with cardiac hypertrophy were accompanied by the discovery of natriuretic peptides in the heart.4,5 Since then, this has been followed by characterization of regulatory mechanisms in natriuretic peptide secretion and synthesis and further insight of the signaling mechanisms and of the development of cardiac hypertrophy has been achieved.

Regulatory Peptides, Apr 1, 2003

Adrenomedullin (AM) may function as an autocrine and/or paracrine factor in the heart, but the ex... more Adrenomedullin (AM) may function as an autocrine and/or paracrine factor in the heart, but the exact mechanisms regulating cardiac AM gene expression are unknown. The aim of the present study was to characterize the role of mechanical load in regulating gene expression of AM by using two hypertensive rat strains as experimental models. Acute pressure overload was produced by arginine 8-vasopressin (AVP, 0.05 Ag/kg/min, i.v.) infusion in conscious spontaneously hypertensive rats (SHR) and double transgenic rats (dTGR) harboring both the human renin and angiotensinogen genes and in their respective normotensive strains. A significant increase in left ventricular AM mRNA levels was seen in the left ventricles of all rat strains, the increase being augmented in hypertensive strains. Direct left ventricular wall stretch in isolated, perfused rat heart preparation also activated AM gene expression. However, stretching of cultured neonatal ventricular myocytes resulted in inhibition of AM gene expression, and stretch also blocked hypoxia-induced increase in AM gene expression. The present study shows that cardiac AM gene expression is upregulated in response to pressure overload and that this upregulation may be mediated via cell types other than cardiac myocytes.

During cardiac hypertrophy individual cardiac myocytes increase in size, which is accompanied by ... more During cardiac hypertrophy individual cardiac myocytes increase in size, which is accompanied by augmented protein synthesis and selective induction of a subset of genes. These phenotypic changes of myocytes are a result from altered intracellular signaling mechanisms and molecules. B-type natriuretic peptide (BNP) gene was selected as a target gene for the study of cardiac signaling mechanisms, since it is activated by mechanical, neural and humoral stimuli during myocyte hypertrophy. To generate hypertrophy of cardiac myocytes, neonatal rat cardiac myocytes were subjected to exogenous hypertrophic agonists such as endothelin-1 (ET-1) or to cyclic mechanical stretch. The role and regulation of transcription factors were studied by utilizing promoter analysis together with site-specific mutations and measurement of DNA binding activity and phosphorylation. GATA-4 mediated signaling was inhibited by blocking DNA binding with decoy oligonucleotides or by decreasing GATA-4 synthesis via adenoviral antisense delivery. ET-1 activated GATA-4 via serine residue phosphorylation, and this effect was mediated via p38 kinase. Similarly, GATA-4 binding activity was increased by ET-1 and mechanical stretch, but it was essential for activation of BNP gene only in the latter stimulation. Importantly, downregulation of GATA-4 protein levels prevented mechanical stretch induced hypertrophy of cardiac myocytes. In contrast, separate mechanism for an ET-1 specific signaling was composed of p38 kinase regulated ETS-like transcription factor-1 (Elk-1). Finally, the effect of mechanical stretch on endogenous endothelin-1 (ET-1) synthesis in cardiac cells was studied. Intrinsic ET-1 synthesis was activated in stretched cardiac myocytes, yet the levels of ET-1 were relatively low. This work suggests that GATA-4 transcription factor is required for mechanical stretch mediated hypertrophic program, and Elk-1 may act as a downstream effector of ET-1 in cardiac myocytes. Taken together, induction of ET-1 and BNP genes as well as activation of GATA-4 and Elk-1 transcription factors are regulated via a network of mitogen activated protein kinase pathways.

Journal of Molecular Medicine, 2002

GATA-4 transcription factor is required for normal cardiac development. However, it is unknown wh... more GATA-4 transcription factor is required for normal cardiac development. However, it is unknown whether GATA-4 is an essential mediator of hypertrophic responses in the heart. Rat B-type natriuretic peptide (BNP) gene promoter contains a region of two adjacent GATA binding sites (between-68 and-97) with high affinity for GATA-4. In order to block GATA-4 dependent signaling in cultured neonatal rat ventricular myocytes we administered a synthetic 30-bp phosphorothioated double-stranded DNA complementary to the rat BNP promoter region (between-68 and-97) as a "decoy" ciselement to bind GATA-4. GATA decoy oligodeoxynucleotide treatment of cardiomyocytes blocked GATA-4 DNA binding activity in electrophoretic mobility shift analysis and decreased baseline expression of cardiac natriuretic peptides and GATA-dependent promoter activity. In contrast, blocked GATA-4 DNA binding did not prevent endothelin-1 or phenylephrine induced expression of cardiac natriuretic peptides. Mutation of GATA binding sites at-80 and-91 rat BNP promoter downregulated baseline but did not affect endothelin-1 or angiotensin II induced promoter activity. Additively, GATA decoy oligodeoxynucleotide treatment was insufficient to block endothelin-1 induced activation of protein synthesis or sarcomeric protein assembly. In conclusion, a targeted disruption of GATA-4 DNA binding activity is insufficient to prevent hypertrophic agonist induced responses of ventricular myocytes.

Scandinavian Journal of Surgery, Feb 8, 2023

Background and objective: Acute mesenteric ischemia (AMI) has a high mortality rate due to the de... more Background and objective: Acute mesenteric ischemia (AMI) has a high mortality rate due to the development of bowel necrosis. Patients are often ruled outside active care if a large proportion of small bowel is necrotic. With the development of treatment for short bowel syndrome (SBS) and intestinal transplantation methods, long-term survival is possible even after extensive small bowel resections. This study aims to assess the incidence of SBS and potentially suitable candidates for intestinal transplantation among patients treated for AMI. Methods: This population-based retrospective study comprised patients aged less than 70 years and diagnosed with AMI between January 2006 and October 2020 in Helsinki and Uusimaa health care district, Finland. Results: Altogether, AMI was diagnosed in 711 patients, of whom 133 (19%) were aged below 70. An intervention was performed in 110 (83%) patients. Of these 133 patients, 16 (12%) were ruled outside active treatment due to extensive small bowel necrosis at exploratory laparotomy, of whom 6 (5%) were potentially suitable for intestinal transplantation. Two patients were considered as potential candidates for intestinal transplantation at bowel resection but died of AMI. Nine (7%) patients needed parenteral nutrition after resection, and two of them (2%) developed SBS. Only one patient needed long-term parenteral nutrition after hospital discharge. This patient remained dependent on parenteral nutrition but died before evaluation of intestinal transplantation could be carried out while the other patient was able to return to enteral nutrition. Conclusions: A small number of patients with AMI below 70 years of age are potentially eligible for intestinal transplantation.

Journal of Biological Chemistry, Oct 1, 2009

The Mdm2 ubiquitin ligase is an important regulator of p53 abundance and p53-dependent apoptosis.... more The Mdm2 ubiquitin ligase is an important regulator of p53 abundance and p53-dependent apoptosis. Mdm2 expression is frequently regulated by a p53 Mdm2 autoregulatory loop whereby p53 stimulates Mdm2 expression and hence its own degradation. Although extensively studied in cell lines, relatively little is known about Mdm2 expression in heart where oxidative stress (exacerbated during ischemia-reperfusion) is an important pro-apoptotic stimulus. We demonstrate that Mdm2 transcript and protein expression are induced by oxidative stress (0.2 mM H 2 O 2) in neonatal rat cardiac myocytes. In other cells, constitutive Mdm2 expression is regulated by the P1 promoter (5 to exon 1), with inducible expression regulated by the P2 promoter (in intron 1). In myocytes, H 2 O 2 increased Mdm2 expression from the P2 promoter, which contains two p53-response elements (REs), one AP-1 RE, and two Ets REs. H 2 O 2 did not detectably increase expression of p53 mRNA or protein but did increase expression of several AP-1 transcription factors. H 2 O 2 increased binding of AP-1 proteins (c-Jun, JunB, JunD, c-Fos, FosB, and Fra-1) to an Mdm2 AP-1 oligodeoxynucleotide probe, and chromatin immunoprecipitation assays showed it increased binding of c-Jun or JunB to the P2 AP-1 RE. Finally, antisense oligonucleotide-mediated reduction of H 2 O 2-induced Mdm2 expression increased caspase 3 activation. Thus, increased Mdm2 expression is associated with transactivation at the P2 AP-1 RE (rather than the p53 or Ets REs), and Mdm2 induction potentially represents a cardioprotective response to oxidative stress. Exposure of cardiac myocytes to sufficiently high levels of reactive oxygen species (ROS) 6 such as H 2 O 2 leads to their □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3 and an additional reference. 1 Supported by fellowships from the Sigrid Jusé lius Foundation, the Finnish Foundation for Cardiovascular Research, the Instrumentarium Foundation, the Aarne and Aili Turunen Foundation, the Maud Kuistila Foundation, and the Paavo Nurmi Foundation. 2 Held a United Kingdom Medical Research Council Studentship for Training in Research Methods.

Pitkittynyt ripuli on yleinen vaiva, jonka taustalla voi olla elimellinen tai toiminnallinen syy.... more Pitkittynyt ripuli on yleinen vaiva, jonka taustalla voi olla elimellinen tai toiminnallinen syy. Kliinispatologisessa kokouksessa käytiin eri alojen asiantuntijoiden kanssa yhdessä läpi 58-vuotiaan pit kitty nyttä ripulia sairastavan naisen tapausta. Ripuli johti toistuviin päivystyskäynteihin ja vuodeosastohoitoon. Diagnoosiin pääsy edellytti monien muiden sairauksien poissulkemista ja yhteistyötä erikoisalojen välillä. Ripulin syyksi selvisi harvinainen sairaus, johon löytyi myös tehokas hoito.

Temporal regulation of expression of immediate early and second phase transcripts by endothelin-1... more Temporal regulation of expression of immediate early and second phase transcripts by endothelin-1 in cardiomyocytes

The American Journal of Gastroenterology, Feb 8, 2019

Common variable immunodeficiency (CVID) is associated with a spectrum of autoimmune complications... more Common variable immunodeficiency (CVID) is associated with a spectrum of autoimmune complications. We studied the prevalence of gastrointestinal (GI) manifestations and infections in patients with CVID. METHODS: Complete clinical data of 132 Finnish patients with CVID (106 probable and 26 possible CVID) followed up between 2007 and 2016 were collected to a structured database. Data on endoscopies, histology, and laboratory studies were retrieved from patient files. RESULTS: Most common referral indications were diarrhea and/or weight loss (47%-67%). Patients with probable CVID had higher fecal calprotectin and a1-antitrypsin and lower blood vitamin B12 than patients with possible CVID. Gastroscopy and colonoscopy were done to 71 (67%) and 63 (59%) patients with probable CVID, respectively. Endoscopies showed that 15% of them had chronic active gastritis and 17% atrophic gastritis and 3% had gastric adenocarcinoma. A celiac sprue-like condition was found in 7 patients (10%), of whom 3 responded to a gluten-free diet. Colonoscopies demonstrated unspecific colitis (14%), ulcerative colitis (8%), microscopic colitis (10%), and Crohn's disease (2%). Colonic polyps were noted in 30% of patients, and 3% had lower GI malignancies. Thirty-five patients with CVID had bacterial or parasitic gastroenteritis; chronic norovirus was detected in 4 patients with probable CVID. Patients with GI inflammation had higher levels of fecal calprotectin and blood CD8 1 T lymphocytes but lower counts of CD19 1 CD27 1 memory B cells and/or CD19 1 B cells. Immunophenotype with low B-cell counts was associated with higher fecal calprotectin levels. DISCUSSION: Patients with CVID had a high prevalence of GI manifestations and infections of the GI tract. GI inflammation was associated with a distinct immunophenotype and elevated fecal calprotectin.

Cardiomyocytes were unstimulated (Control), exposed to cycloheximide (CX) alone, or to ET-1 (ET) ... more Cardiomyocytes were unstimulated (Control), exposed to cycloheximide (CX) alone, or to ET-1 (ET) in the absence or presence of cycloheximide for 1 h (solid bars) or 2 h (open bars). RNAs in CXS1, CXS2 and CXS3 (whose induction by ET-1 was further increased by cycloheximide), and CX1a, CX1b and CX1c (whose induction was not inhibited by cycloheximide) were classified as immediate early gene RNAs. CX2a, CX2b, CX2c and CX2d RNAs showed partial inhibition of the response to ET-1 at 1 h by cycloheximide and are probably second phase RNAs. CX3a and CX3b RNAs were clearly second phase RNAs with >80% inhibition of the response to ET-1 by cycloheximide. The numbers of transcripts in each cluster are shown in parentheses. Statistical significance (repeated measures one-way ANOVA with Tukey post-test) < 0.05 for Control versus ET-1 (2 h; all clusters), Control versus ET-1 (1 h; all clusters except CXS3, CX1c, CX2d and CX3b), Control versus CX (1 or 2 h; all clusters in (a)), ET-1 (2 h) v...

Pacing-induced calcineurin activation controls cardiac Ca2+

The 1,494 probesets identified as significantly (FDR <b>Copyright information:</b>Tak... more The 1,494 probesets identified as significantly (FDR <b>Copyright information:</b>Taken from "Temporal regulation of expression of immediate early and second phase transcripts by endothelin-1 in cardiomyocytes"http://genomebiology.com/2008/9/2/R32Genome Biology 2008;9(2):R32-R32.Published online 14 Feb 2008PMCID:PMC2374717.

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