CELLULAR NEUROCIENCE | NEURONAL SIGNALING | CARDIOVASCULAR RESEARCH | METABOLISM | LIPID SIGNALING AND HOMEOSTASIS | ENDOCRINOLOGY | CELLULAR PHYSIOLOGY | TARGETED GENE-EXPRESSION ANALYSIS | MEMBRANE BIOLOGY | TELOMERE RESEARCH
Ilkka Tikkanen, MD, PhD, Professor, Head
Päivi Lakkisto, MD, PhD, Adjunct Professor, Co-Head
Mika Laine, MD, PhD, Adjunct Professor
Jere Paavola, MD, PhD
Hong Wang, MSc, PhD
Heli Segersvärd, MD
Juuso Siren, MD
Karri Kalervo, MD
Mikko Hänninen, MD
Suneeta Narumanchi, MSc
Katariina Immonen, BSc, Laboratory Technician
Riikka Kosonen, MSc, Laboratory Technician
Sanni Perttunen, BSc, Laboratory Technician
Our research group studies mechanisms of end organ damage in cardiovascular and renal diseases. In addition, the cardiovascular and renal protective properties of new cardiovascular drugs and treatments have been evaluated. During recent years, the group’s research has focused on exploring the molecular mechanisms of cardiac injury, regeneration, and repair after myocardial infarction and in heart failure, to identify potential targets for cardiovascular medicines. In these studies, a translational approach is applied, combining methods and findings of both basic science and clinical research in order to improve the evaluation and treatment of cardiovascular diseases.
The role of heme oxygenase-1 (HO-1) in cardiovascular diseases
HO-1 and its reaction products, carbon monoxide (CO), biliverdin, and bilirubin have a variety of cardiovascular protective properties. In the rat myocardial infarction (MI) model, HO-1 and CO protect the heart against ischemic injury and enhance cardiac repair. Our recent findings have demonstrated that treatment with a specific CO-donor, CORM-3, improves both structural and functional cardiac recovery after MI in rats. These effects were associated with altered expression of myocardial microRNAs, notably miR-206, involved in cardiac remodeling and repair. The modulation of the HO-1-CO pathway may prove to be a novel tool to facilitate cardiac recovery after myocardial injury and protect against development of heart failure after MI.
In collaboration with Adj. Prof. Hannele Laivuori, University of Helsinki (HU), we have studied the association of HO-1 gene (HMOX1) polymorphisms and risk of preeclampsia. The long allele of maternal microsatellite GTn repeat seems to predispose to a late-onset, less severe form of preeclampsia whereas the long fetal GTn repeat may instead increase the mother’s risk of severe and early-onset preeclampsia.
We are collaborating with Prof. Per-Henrik Groop and the FinnDiane Study Group, HU, Helsinki University Hospital (HUCH), and Folkhälsan Institute of Genetics, to study the possible involvement of HO-1 and HO-1 gene polymorphisms in the development of cardiovascular and renal complications in type 1 diabetes.
Molecular mechanisms of cardiac failure, hypertrophy, and repair
The prognosis of chronic cardiac failure is still poor despite optimal therapy with currently available cardiovascular drugs. Thus, deeper understanding of cellular and molecular mechanisms of cardiac failure, regeneration, and repair is needed.
Septins are small GTPases that are associated with actin and are important in the organization of cytoskeleton. In collaboration with Prof. Sanna Lehtonen, HU, we were able to show for the first time that septin7b, the zebrafish ortholog of human septin7, is essential for the subcellular organization of cardiomyocytes and cardiac function in zebrafish. Moreover, knock-down of septin7b diminishes the expression of retinaldehyde dehydrogenase 2 (raldh2), which catalyzes the synthesis of retinoic acid shown to modulate ischemic injury and stimulate cardiac regeneration.
Vezf1 encodes a nuclear protein containing six zinc finger motifs of the C2H2-type (krüppel-like) and a proline-rich transcriptional transactivation domain. In collaboration with Prof. Risto Kerkelä, University of Oulu, we investigated the role of Vezf1 in regulating stress-induced cardiac hypertrophy and development of heart failure employing loss of function methods in embryonic zebrafish by using antisense oligomer molecules that block the translation or splicing of Vezf1. Our preliminary results demonstrate that Vezf1 regulates the development of stress-induced cardiac hypertrophy by modulating βMHC expression and cardiac contractile function by stabilizing cardiomyocyte calcium cycling. Our results indicate a clinically relevant role for Vezf1 in the heart.
MicroRNAs are short noncoding RNA molecules widely involved in the regulation of gene expression. Based on initial RT-PCR array screening of experimental and clinical materials, followed by quantitative RT-PCR, several novel cardiovascular miRNAs of interest were identified. In collaboration with Adj Prof. Veli-Pekka Harjola, HUCH, and Dr. Yvan Devaux, Luxembourg Institute of Health, Luxembourg, we were able to show that high plasma levels of miR-423-5p predict mortality in patients with acute cardiogenic shock.
Figure. Immunostaining of zebrafish heart at 3 days post fertilization showing
cell membranes (ZN-5, green) and nuclei (mef-2, red)(courtesy of Sanni Perttunen).
We are using the cardiac cryoinfarction model in adult zebrafish to study the effects of micro-RNAs on cardiac regeneration and repair. We have validated protocols for efficient delivery on Mirs and Antagomirs to the adult zebrafish. This method enables the study of molecules and pathways related to cardiac repair in a fast-growing, affordable model organism with an amazing regenerative capacity. Additionally, we have developed a drug-induced cardiac hypertrophy/failure model in embryonic zebrafish. With easy delivery of drugs and methodology for gene silencing, including CRISPR/Cas9-mediated gene editing, our models will provide a robust platform for studying the development of cardiac hypertrophy and failure, as well as factors affecting recovery of cardiac function from heart failure.
High blood pressure is the leading risk factor for death worldwide. Despite the development of antihypertensive therapies during recent years, treatment results are still unsatisfactory.
During the last year, our clinical hypertension research has focused on new treatment strategies for resistant hypertension, notably renal denervation and baroreflex activation therapy. In addition, we have participated in international collaboration to elucidate the blood pressure lowering and vascular effects of sodium glucose co-transporter 2 (SGLT2) inhibitors, novel glucose-lowering drugs with cardiovascular and renal protective properties, in the treatment of type 2 diabetes.
Our group is participating in several collaborative clinical studies on cardiovascular and renal diseases including acute and chronic heart failure as well as acute kidney injury.
Ilkka Tikkanen, MD, PhD, Professor
Jäntti T, Segersvärd H, Tarvasmäki T, Lassus J, Devaux Y, Vausort M, Pulkki K, Sionis A, Bayes-Genis A, Tikkanen I, Lakkisto P, Harjola V-P. Circulating levels of microRNA 423-5p are associated with 90-day mortality in cardiogenic shock. ESC Heart failure, 2018, in press.
Cherney DZI, Cooper ME, Tikkanen I, Pfarr E, Johansen OE, Woerle HJ, Broedl UC, Lund SS. Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int 2018; 93: 231-244.
Lalowski MM, Björk S, Finckenberg P, Soliymani R, Tarkia M, Calza G, Blokhina D, Tulokas S, Kankainen M, Lakkisto P, Baumann M, Kankuri E, Mervaala E. Characterizing the key metabolic pathways of the neonatal mouse heart using a quantitative combinatorial omics approach. Front Physiol 2018, 11:935 doi: 10.3389/fphys.2018.00365.
Kaartokallio T, Utge S, Klemetti MM, Paananen J, Pulkki K, Romppanen J, Tikkanen I, Heinonen S, Kajantie E, Kere J, Kivinen K, Pouta A, Lakkisto P, Laivuori H. Fetal microsatellite in the heme oxygenase 1 promoter is associated with severe and early-onset preeclampsia. Hypertension 2018; 71: 95-102.
Segersvärd H, Lakkisto P, Hänninen M, Forsten H, Siren J, Immonen K, Kosonen R, Sarparanta M, Laine M, Tikkanen I. Carbon monoxide releasing molecule improves structural and functional cardiac recovery after myocardial injury. Eur J Pharmacol 2018; 818: 57-66.
Dash SN, Narumanchi S, Paavola J, Perttunen S, Wang H, Lakkisto P, Tikkanen I, Lehtonen S. Sept7b is required for the subcellular organization of cardiomyocytes and cardiac function in zebrafish. Am J Physiol Heart Circ Physiol 2017; 312: H1085-H1095.
Gordin D, Fadl Elmula FEM, Andersson B, Gottsäter A, Elf J, Kahan T, Christensen KL, Vikatmaa P, Vikatmaa L, Bastholm Olesen T, Groop PH, Olsen MH, Tikkanen I; Nordic BAT Study Group. The effects of baroreflex activation therapy on blood pressure and sympathetic function in patients with refractory hypertension: the rationale and design of the Nordic BAT study. Blood Pressure 2017; 26: 294-302.
Siren J, Vaahersalo J, Skrifvars M, Pettilä V, Tiainen M, Tikkanen I, Lakkisto P; FINNRESUSCI Study Group. Plasma heme oxygenase-1 in patients resuscitated from out-of-hospital cardiac arrest. Shock. 2016; 45(3):320-5.
Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, Johansen OE. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015; 17:1180-1193.
Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, Woerle HJ; on behalf of the EMPA-REG BP Investigators. Empagliflozin Reduces Blood Pressure in Patients With Type 2 Diabetes and Hypertension. Diabetes Care. 2015; 38:420-428.
Kaartokallio T, Klemetti MM, Timonen A, Uotila J, Heinonen S, Kajantie E, Kere J, Kivinen K, Pouta A, Lakkisto P, Laivuori H. Microsatellite polymorphism in the heme oxygenase-1 promoter is associated with nonsevere and late-onset preeclampsia. Hypertension. 2014; 64:172-77.
Paavola J, Schliffke S, Rossetti S, Kuo IY, Yuan S, Sun Z, Harris PC, Torres VE, Ehrlich BE. Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. J Mol Cell Cardiol 58:199-208, 2013.
Lakkisto P, Siren J-M, Kytö V, Forsten H, Laine M, Pulkki K, Tikkanen I. Heme oxygenase-1 induction protects the heart and modulates cellular and extracellular remodeling after myocardial infarction in rats. Exp Biol Med. 2011; 236:1437-1448.
Lakkisto P, Kytö V, Forsten H, Siren JM, Segersvärd H, Voipio-Pulkki LM, Laine M, Pulkki K, Tikkanen I. Heme oxygenase-1 and carbon monoxide promote neovascularization after myocardial infarction by modulating the expression of Hif-1a, SDF-1a and VEGF-B. Eur J Pharmacol. 2010; 635: 156-164.
Kitabayashi K, Siltanen A, Pätilä T, Mahar MA, Tikkanen I, Koponen J, Ono M, Sawa Y, Kankuri E, Harjula A. Bcl-2 expression enhances myoblast sheet transplantation therapy for acute myocardial infarction. Cell Transplant. 2010; 19: 573-588.
Paavola J, Viitasalo M, Laitinen-Forsblom PJ, Pasternack M, Swan H, Tikkanen I, Toivonen L, Kontula K, Laine M. Mutant ryanodine receptors in catecholaminergic polymorphic ventricular tachycardia generate delayed afterdepolarizations due to increased propensity to Ca2+ waves. Eur Heart J. 2007; 28: 1135-1142.
Pörsti I, Fan M, Kööbi P, Jolma P, Kalliovalkama J, Vehmas TI, Helin H, Holthöfer H, Mervaala E, Nyman T, Tikkanen I. High calcium diet down-regulates kidney angiotensin-converting enzyme in experimental renal failure. Kidney Int. 2004; 66: 2155-2166.