Franz Hofmann

Institut für Pharmakologie und Toxikologie der Bundeswehr, München, Bavaria, Germany

Are you Franz Hofmann?

Claim your profile

Publications (472)2762.58 Total impact

  • Source
    Elisabeth Angermeier · Katrin Domes · Franz Hofmann ·

    BMC pharmacology & toxicology 09/2015; 16(Suppl 1):A35-A35. DOI:10.1186/2050-6511-16-S1-A35

  • BMC pharmacology & toxicology 09/2015; 16(Suppl 1):A99-A99. DOI:10.1186/2050-6511-16-S1-A99

  • BMC pharmacology & toxicology 09/2015; 16(Suppl 1):A23-A23. DOI:10.1186/2050-6511-16-S1-A23
  • F Limmer · E Schinner · H Castrop · H Vitzthum · F Hofmann · J Schlossmann ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Sodium chloride reabsorption in the thick ascending limb of the loop of Henle is mediated by the Na(+) -K(+) -2Cl(-) cotransporter (NKCC2). The loop diuretic furosemide is a potent inhibitor of NKCC2. However, less is known about the mechanism regulating the electrolyte transporter. Considering the well-established effects of nitric oxide on NKCC2 activity, cGMP is likely involved in this regulation. cGKI (PKG, cGMP dependent protein kinase I) is a cGMP target protein that phosphorylates different substrates after activation through cGMP. We investigated the potential correlation between the cGMP / cGKI pathway and NKCC2 regulation. We treated wild type (wt) and cGKIα-rescue mice with furosemide. cGKIα-rescue mice expressed cGKIα only under the control of the smooth muscle specific transgelin (SM22) promoter in a cGKI deficient background. Furosemide treatment increased the urine excretion of sodium and chloride in cGKIα-rescue mice compared to that in wt mice. We analysed the phosphorylation of NKCC2 by Western blotting and immunostaining using the phosphospecific antibody R5. The administration of furosemide significantly increased the phosphorylated NKCC2 signal in wt but not in cGKIα-rescue mice. NKCC2 activation led to its phosphorylation and membrane translocation. To examine whether cGKI was involved in this process, we analysed VASP (vasodilator-stimulated phosphoprotein), which is phosphorylated by cGKI. Furosemide injection resulted in increased VASP phosphorylation in wt mice. We hypothesize that furosemide administration activated cGKI, leading to NKCC2 phosphorylation and membrane translocation. This cGKI-mediated pathway could be a mechanism to compensate for the inhibitory effect of furosemide on NKCC2. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    FEBS Journal 07/2015; DOI:10.1111/febs.13376 · 4.00 Impact Factor
  • Franz Hofmann · Anouar Belkacemi · Veit Flockerzi ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Voltage gated calcium channels (Cav) are composed of up to five proteins: The ion conducting pore subunit α1 and the auxiliary subunits α2, δ, β, and γ. Recent reports show that Cav α 1 and Cavβ comprise the calcium channel core complex and that β, α 2δ and γ may serve additional roles that are independent of the Cavα1 subunit. The T-type calcium channels may be composed of only a Cav α1 subunit. This short review will summarize these emerging functions.
    Current Molecular Pharmacology 05/2015; 8(2). DOI:10.2174/1874467208666150507110202
  • Source
    R Bangalore · G Mehrke · K Gingrich · F Hofmann · R S Kass ·

  • [Show abstract] [Hide abstract]
    ABSTRACT: Signaling via cGMP-dependent protein kinase I (cGKI) and canonical transient receptor potential (TRPC) channels appears to be involved in the regulation of cardiac hypertrophy. Recent evidence suggests that TRPC channels are targets for cGKI, and phosphorylation of these channels may mediate the antihypertrophic effects of cGMP signaling. We tested this concept by investigating the role of cGMP/cGKI signaling on angiotensin II (A II)-induced cardiac hypertrophy using a control group (Ctr), trpc6−/−, trpc3−/−, trpc3−/−/6−/−, βRM mice, and trpc3−/−/6−/− × βRM mice. βRM mice express cGKIβ only in the smooth muscle on a cGKI−/− background. The control group was composed of littermate mice that contained at least one wild type gene of the respective genotype. A II was infused by minipumps (7 days; 2 mg/kg/day) in Ctr, trpc6−/−, trpc3−/−, trpc3−/−/6−/−, βRM, and trpc3−/−/6−/− × βRM mice. Hypertrophy was assessed by measuring heart weight per tibia length (HW/TL) and fibrosis by staining of heart slices. A II-induced increase in HW/TL and fibrosis was absent in trpc3−/− mice, whereas an increase in HW/TL and fibrosis was evident in Ctr and trpc6−/−, minimal or absent in trpc3−/−, moderate in βRM, and dramatic in trpc3−/−/6−/− βRM mice. These results suggest that TRPC3 may be necessary for A II-induced cardiac hypertrophy. On the other hand, hypertrophy and fibrosis were massively increased in βRM mice on a TRPC3/6 × cGKI−/−KO background, indicating an “additive” coupling between both signaling pathways.
    Pflügers Archiv - European Journal of Physiology 12/2014; 467(10). DOI:10.1007/s00424-014-1682-0 · 4.10 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The voltage-gated Ca(2+) (CaV) channel acts as a key player in β cell physiology and pathophysiology. β cell CaV channels undergo hyperactivation subsequent to exposure to type 1 diabetic (T1D) serum resulting in increased cytosolic free Ca(2+) concentration and thereby Ca(2+)-triggered β cell apoptosis. The present study was aimed at revealing the subtypes of CaV1 channels hyperactivated by T1D serum as well as the biophysical mechanisms responsible for T1D serum-induced hyperactivation of β cell CaV1 channels. Patch-clamp recordings and single-cell RT-PCR analysis were performed in pancreatic β cells from CaV1 channel knockout and corresponding control mice. We now show that functional CaV1.3 channels are expressed in a subgroup of islet β cells from CaV1.2 knockout mice (CaV1.2(-/-)). T1D serum enhanced whole-cell CaV currents in islet β cells from CaV1.3 knockout mice (CaV1.3(-/-)). T1D serum increased the open probability and number of functional unitary CaV1 channels in CaV1.2(-/-) and CaV1.3(-/-) β cells. These data demonstrate that T1D serum hyperactivates both CaV1.2 and CaV1.3 channels by increasing their conductivity and number. These findings suggest CaV1.2 and CaV1.3 channels as potential targets for anti-diabetes therapy.
    Cellular and Molecular Life Sciences CMLS 10/2014; 72(6). DOI:10.1007/s00018-014-1737-6 · 5.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The presence of cGMP-dependent protein kinase I (cGKI) in murine adipocytes has been questioned, although cGKI was implicated in the thermogenic program of fat cells (FCs) and to exert anti-hypertrophic/-inflammatory effects in white adipose tissue. Herein, cGKI was detected in adipocytes from control mice, whereas FCs from global cGKI knockouts (cGKI(-/-)) and cGKIα rescue (αRM) mice remained cGKI-negative. cGKI mutants exhibit decreased adipocyte size, plasma leptin levels and reduced body-weights as compared to litter-matched controls. Low abundance of adiponectin in WAT and plasma of αRM animals together with previously confirmed high IL-6 levels indicate a low-grade inflammation. However, αRMs were protected from streptozotocin-induced hyperglycemia. Our results suggest that cGMP/cGKI affects both glucose and FC homeostasis in more complex mode than previously thought.
    Biochemical and Biophysical Research Communications 08/2014; 452(1). DOI:10.1016/j.bbrc.2014.08.071 · 2.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Conflicting results have been reported for the roles of cGMP and cGMP-dependent protein kinase I (cGKI) in various pathological conditions leading to cardiac hypertrophy and fibrosis. A cardioprotective effect of cGMP/cGKI has been reported in whole animals and isolated cardiomyocytes, but recent evidence from a mouse model expressing cGKIβ only in smooth muscle (βRM) but not in cardiomyocytes, endothelial cells, or fibroblasts has forced a reevaluation of the requirement for cGKI activity in the cardiomyocyte antihypertrophic effects of cGMP. In particular, βRM mice developed the same hypertrophy as WT controls when subjected to thoracic aortic constriction or isoproterenol infusion. Here, we challenged βRM and WT (Ctr) littermate control mice with angiotensin II (AII) infusion (7 d; 2 mg⋅kg(-1)⋅d(-1)) to induce hypertrophy. Both genotypes developed cardiac hypertrophy, which was more pronounced in Ctr animals. Cardiomyocyte size and interstitial fibrosis were increased equally in both genotypes. Addition of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, in the drinking water had a small effect in reducing myocyte hypertrophy in WT mice and no effect in βRM mice. However, sildenafil substantially blocked the increase in collagen I, fibronectin 1, TGFβ, and CTGF mRNA in Ctr but not in βRM hearts. These data indicate that, for the initial phase of AII-induced cardiac hypertrophy, lack of cardiomyocyte cGKI activity does not worsen hypertrophic growth. However, expression of cGKI in one or more cell types other than smooth muscle is necessary to allow the antifibrotic effect of sildenafil.
    Proceedings of the National Academy of Sciences 08/2014; 111(35). DOI:10.1073/pnas.1414364111 · 9.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mouse pancreatic β- and α-cells are equipped with voltage-gated Na+ currents that inactivate over widely different membrane potentials (half-maximal inactivation [V0.5] at -100 mV and -50 mV in β- and α-cells, respectively). Single-cell PCR analyses show that both α- and β-cells have Nav1.3 (Scn3) and Nav1.7 (Scn9a) α-subunits, but their relative proportions differ: β-cells principally express Nav1.7 and α-cells Nav1.3. In α-cells, genetically ablating Scn3a reduces the Na+ current by 80%. In β-cells, knockout of Scn9a lowers the Na+ current by >85%, unveiling a small Scn3a-dependent component. Glucagon and insulin secretion are inhibited in Scn3a−/− islets but unaffected in Scn9a-deficient islets. Thus Nav1.3 is the functionally important Na+ channel α-subunit in both α- and β-cells because Nav1.7 is largely inactive at physiological membrane potentials due to its unusually negative voltage dependence of inactivation. Interestingly, the Nav1.7 sequence in brain and islets is identical and yet the V0.5 for inactivation is >30mV more negative in β-cells. This may indicate the presence of an intracellular factor that modulates the voltage dependence of inactivation.This article is protected by copyright. All rights reserved
    The Journal of Physiology 08/2014; 592(21). DOI:10.1113/jphysiol.2014.274209 · 5.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Within the suprachiasmatic nucleus (SCN) of the hypothalamus, circadian timekeeping and resetting have been shown to be largely dependent on both membrane depolarization and intracellular second-messenger signaling. In both of these processes, voltage-gated calcium channels (VGCCs) mediate voltage-dependent calcium influx, which propagates neural impulses by stimulating vesicle fusion and instigates intracellular pathways resulting in clock gene expression. Through the cumulative actions of these processes, the phase of the internal clock is modified to match the light cycle of the external environment. To parse out the distinct roles of the L-type VGCCs, we analyzed mice deficient in Cav1.2 (Cacna1c) in brain tissue. We found that mice deficient in the Cav1.2 channel exhibited a significant reduction in their ability to phase-advance circadian behavior when subjected to a light pulse in the late night. Furthermore, the study revealed that the expression of Cav1.2 mRNA was rhythmic (peaking during the late night) and was regulated by the circadian clock component REV-ERBα. Finally, the induction of clock genes in both the early and late subjective night was affected by the loss of Cav1.2, with reductions in Per2 and Per1 in the early and late night, respectively. In sum, these results reveal a role of the L-type VGCC Cav1.2 in mediating both clock gene expression and phase advances in response to a light pulse in the late night.
    Journal of Biological Rhythms 08/2014; 29(4):288-98. DOI:10.1177/0748730414540453 · 2.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: cGMP inhibits hypertrophy, decreases fibrosis, and protects against cardiac ischemia-reperfusion (I/R) injury. Gene-targeting studies have not defined a clear role for its major downstream effector, cGMP-dependent protein kinase I (cGKI), in cardiac hypertrophy, but do implicate cGMP-cGKI signaling in fibrosis and I/R injury. No direct cGKI activators have advanced to clinical trials, whereas cardiac trials of agents that modulate cGMP via particulate or soluble guanylyl cyclases (GCs) and phosphodiesterase 5 (PDE5) are ongoing. Here we review concerns arising from preclinical and clinical studies that question whether targeting the cGMP pathway remains an encouraging concept for management of heart dysfunction. So far, trial results for GC modulators are inconclusive, and sildenafil, a PDE5 inhibitor, although cardioprotective in mouse models, has not shown positive clinical results. Preclinical cardioprotection observed for sildenafil may result from inhibition of PDE5 in non-cardiomyocytes or off-target effects, possibly on PDE1C. On the basis of such mechanistic considerations, re-evaluation of the cellular localization of drug target(s) and intervention protocols for cGMP-elevating agents may be needed.
    Trends in Pharmacological Sciences 06/2014; 35(8). DOI:10.1016/ · 11.54 Impact Factor
  • Source

    Gastroenterology 05/2014; 146(5):S-651-S-652. DOI:10.1016/S0016-5085(14)62368-4 · 16.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Atrial natriuretic peptide (ANP)/cGMPs cause diuresis and natriuresis. Their downstream effectors beyond cGMP remain unclear. To elucidate a probable function of cGMP-dependent protein kinase II (cGKII), we investigated renal parameters in different conditions (basal, salt diets, starving, water load) using a genetically modified mouse model (cGKII-KO), but did not detect any striking differences between WT and cGKII-KO. Thus, cGKII is proposed to play only a marginal role in the adjustment of renal concentration ability to varying salt loads without water restriction or starving conditions. When WT mice were subjected to a volume load (performed by application of a 10-mM glucose solution (3 % of BW) via feeding needle), they exhibited a potent diuresis. In contrast, urine volume was decreased significantly in cGKII-KO. We showed that AQP2 plasma membrane (PM) abundance was reduced for about 50 % in WT upon volume load, therefore, this might be a main cause for the enhanced diuresis. In contrast, cGKII-KO mice almost completely failed to decrease AQP2-PM distribution. This significant difference between both genotypes is not induced by an altered p-Ser256-AQP2 phosphorylation, as phosphorylation at this site decreases similarly in WT and KO. Furthermore, sodium excretion was lowered in cGKII-KO mice during volume load. In summary, cGKII is only involved to a minor extent in the regulation of basal renal concentration ability. By contrast, cGKII-KO mice are not able to handle an acute volume load. Our results suggest that membrane insertion of AQP2 is inhibited by cGMP/cGKII.
    Pflügers Archiv - European Journal of Physiology 01/2014; 466(10). DOI:10.1007/s00424-014-1445-y · 4.10 Impact Factor
  • Franz Hofmann · Veit Flockerzi · Sabine Kahl · Jörg W Wegener ·
    [Show abstract] [Hide abstract]
    ABSTRACT: The L-type Cav1.2 calcium channel is present throughout the animal kingdom and is essential for some aspects of CNS function, cardiac and smooth muscle contractility, neuroendocrine regulation, and multiple other processes. The L-type CaV1.2 channel is built by up to four subunits; all subunits exist in various splice variants that potentially affect the biophysical and biological functions of the channel. Many of the CaV1.2 channel properties have been analyzed in heterologous expression systems including regulation of the L-type CaV1.2 channel by Ca(2+) itself and protein kinases. However, targeted mutations of the calcium channel genes confirmed only some of these in vitro findings. Substitution of the respective serines by alanine showed that β-adrenergic upregulation of the cardiac CaV1.2 channel did not depend on the phosphorylation of the in vitro specified amino acids. Moreover, well-established in vitro phosphorylation sites of the CaVβ2 subunit of the cardiac L-type CaV1.2 channel were found to be irrelevant for the in vivo regulation of the channel. However, the molecular basis of some kinetic properties, such as Ca(2+)-dependent inactivation and facilitation, has been approved by in vivo mutagenesis of the CaV1.2α1 gene. This article summarizes recent findings on the in vivo relevance of well-established in vitro results.
    Physiological Reviews 01/2014; 94(1):303-26. DOI:10.1152/physrev.00016.2013 · 27.32 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: α1-Adrenergic stimulation increases blood vessel tone in mammals. This process involves a number of intracellular signaling pathways that include signaling via phospholipase C, diacylglycerol (DAG), and protein kinase C. So far, it is not certain whether signaling via phospholipase D (PLD) and PLD-derived DAG is involved in this process. We asked whether PLD participates in the α1-adrenergic-mediated signaling in vascular smooth muscle. α1-Adrenergic-induced contraction was assessed by myography of isolated aortic rings and by pressure recordings using the hindlimb perfusion model in mice. The effects of the PLD inhibitor 1-butanol (IC50 0.15 vol%) and the inactive congener 2-butanol were comparatively studied. Inhibition of PLD by 1-butanol reduced specifically the α1-adrenergic-induced contraction and the α1-adrenergic-induced pressure increase by 10 and 40% of the maximum, respectively. 1-Butanol did not influence the aortic contractions induced by high extracellular potassium, by the thromboxane analog U46619, or by a phorbol ester. The effects of 1-butanol were absent in mice that lack PLD1 (Pld1(-/-) mice) or that selectively lack the CaV1.2 channel in smooth muscle (sm-CaV1.2(-/-) mice) but still present in the heterozygous control mice. α1-Adrenergic contraction of vascular smooth muscle involves activation of PLD1, which controls a portion of the α1-adrenergic-induced CaV1.2 channel activity.-Wegener, J. W., Loga, F, Stegner, D., Nieswandt, B., Hofmann, F. Phospholipase D1 is involved in α1-adrenergic contraction of murine vascular smooth muscle.
    The FASEB Journal 11/2013; 28(3). DOI:10.1096/fj.13-237925 · 5.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: α1-adrenergic stimulation increases blood vessel tone in mammals. This process involves a number of intracellular signaling pathways which include signaling via phospholipase C (PLC), diacylglycerol (DAG), and protein kinase C (PKC). So far, it is uncertain whether signaling via phospholipase D (PLD) and PLD-derived DAG is involved in this process. We asked whether PLD participates in the α1-adrenergic-mediated signaling in vascular smooth muscle. Procedures: α1-adrenergic-induced contraction was assessed by myography of isolated aortic rings and by pressure recordings using the hind limb perfusion model in mice. The effects of the PLD inhibitor 1-butanol (IC50 0.15 Vol%) and the inactive congener 2-butanol were comparatively studied. Findings: Inhibition of PLD by 1-butanol reduced specifically α1-adrenergic-induced contraction and α1-adrenergic-induced pressure increase by 10% and 40% of the maximum, respectively. 1-butanol did not influence aortic contractions induced by high extracellular potassium, by the thromboxane analogue U46619, or by a phorbol ester. The effects of 1-butanol were absent in mice that lack PLD1 (Pld1-/- mice) or that selectively lack CaV1.2 channel in smooth muscle (sm-CaV1.2-/- mice) but still present in the heterozygous control mice. Conclusions: α1-adrenergic contraction of vascular smooth muscle involves activation of PLD1 which controls a portion of α1-adrenergic-induced CaV1.2 channel activity.
    The FASEB Journal 11/2013; · 5.04 Impact Factor
  • Source
    Elisabeth Schinner · Armin Kurtz · Franz Hofmann · Jens Schlossmann ·

    BMC Pharmacology 08/2013; 11(1). DOI:10.1186/1471-2210-11-S1-P62 · 1.84 Impact Factor
  • Source

    BMC pharmacology & toxicology 08/2013; 14(Suppl 1):P78. DOI:10.1186/2050-6511-14-S1-P78

Publication Stats

27k Citations
2,762.58 Total Impact Points


  • 1991-2014
    • Institut für Pharmakologie und Toxikologie der Bundeswehr
      München, Bavaria, Germany
    • Technische Universität München
      • Institute of Pharmacology and Toxicology
      München, Bavaria, Germany
  • 1985-2014
    • Universität des Saarlandes
      • • Fachbereich Experimentelle und Klinische Pharmakologie und Toxikologie
      • • Institut für Medizinische Mikrobiologie und Hygiene
      • • Physikalische Chemie
      Saarbrücken, Saarland, Germany
  • 2011
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • Department of Experimental and Clinical Pharmacology and Toxicology
      Erlangen, Bavaria, Germany
  • 1992-2011
    • Deutsches Herzzentrum München
      München, Bavaria, Germany
  • 1999-2010
    • Ludwig-Maximilians-University of Munich
      • • Center for integrated Protein Science Munich (CiPSM)
      • • Institute of Epidemiology and prophylaxis of cardiovascular diseases
      München, Bavaria, Germany
    • Munich Re
      München, Bavaria, Germany
  • 2009
    • University of Southern California
      • Department of Cell and Neurobiology
      Los Angeles, California, United States
  • 2005
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 2004
    • University of Birmingham
      Birmingham, England, United Kingdom
  • 2002
    • Johannes Gutenberg-Universität Mainz
      • Department of Pharmacology
      Mainz, Rhineland-Palatinate, Germany
    • University of Washington Seattle
      • Department of Pharmacology
      Seattle, Washington, United States
  • 1996
    • University of Rochester
      Rochester, New York, United States
  • 1994
    • Tel Aviv University
      • Department of Physiology and Pharmacology
      Tell Afif, Tel Aviv, Israel
  • 1990
    • Baylor College of Medicine
      • Department of Molecular Physiology & Biophysics
      Houston, Texas, United States
    • Ruhr-Universität Bochum
      • Department of Biochemistry Supramolecular Systems
      Bochum, North Rhine-Westphalia, Germany
  • 1989
    • Universitätsklinikum des Saarlandes
      Homburg, Saarland, Germany
  • 1981-1987
    • Universität Heidelberg
      • • Department of Clinical Pharmacology
      • • Institute of Pharmacology
      Heidelburg, Baden-Württemberg, Germany
  • 1980
    • Universität Stuttgart
      • Institute of Biology
      Stuttgart, Baden-Württemberg, Germany