On the contractile function of protein phosphatases in isolated human coronary arteries

Naunyn-Schmiedeberg's Arch Pharmacol

et al. 2023

Self Cite

Cantharidin, an inhibitor of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), is known to increase the force of contraction and shorten the time to relaxation in human ventricular preparations. We hypothesized that cantharidin has similar positive inotropic effects in human right atrial appendage (RAA) preparations. RAA were obtained during bypass surgery performed on human patients. These trabeculae were mounted in organ baths and electrically stimulated at 1 Hz. For comparison, we studied isolated electrically stimulated left atrial (LA) preparations and isolated spontaneously beating right atrial (RA) preparations from wild-type mice. Cumulatively applied (starting at 10 to 30 µM), cantharidin exerted a positive concentration-dependent inotropic effect that plateaued at 300 µM in the RAA, LA, and RA preparations. This positive inotropic effect was accompanied by a shortening of the time to relaxation in human atrial preparations (HAPs). Notably, cantharidin did not alter the beating rate in the RA preparations. Furthermore, cantharidin (100 µM) increased the phosphorylation state of phospholamban and the inhibitory subunit of troponin I in RAA preparations, which may account for the faster relaxation observed. The generated data indicate that PP1 and/or PP2A play a functional role in human atrial contractility.

Section: Clinical Relevancesupporting

confidence: 49%

Cantharidin increases the force of contraction and protein phosphorylation in isolated human atria

Schwarz

Hofmann

Naunyn-Schmiedeberg's Arch Pharmacol

et al. 2023

Self Cite

“…We were interested in not only how they alter the signals leading from the sarcolemmal receptors to the activation of protein kinases but also how they might play a role in the development of cardiac hypertrophy (Boknik et al, 2000) and even heart failure, which we looked at in some initial studies in human hearts (Neumann et al, 1999). In this line, we quite extensively characterized PP2A in humans (Knapp et al, 1999) and animal hearts (Neumann et al, 1993;Gombosova et al, 1998), overexpressed the catalytic subunit of PP2A (Gergs et al, 2004), and studied its role under stressful conditions, such as hypertension-induced hypertrophy (aortic banding) myocardial infarction (Brüchert et al, 2008;Grote-Wessels et al, 2008;Hoehn et al, 2015). Because the H 2 -histamine receptor mediates its effects via cAMP and protein kinase A and phospholamban phosphorylation (Gergs et al, 2019), it seemed logical to test the influence of PP2A on H 2 -histamine receptor-mediated effects because PP2A is known to dephosphorylate phospholamban not only in vitro (Neumann et al, 1993) but also in the beating heart (Gergs et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Stressed Transgenic Mice Overexpressing H₂-Histamine Receptors in the Heart

Kirchhefer

Bergmann

et al. 2020

J Pharmacol Exp Ther

We studied transgenic mice with cardiac-specific overexpression of H 2 -histamine receptors (H 2 -TG) by using the a-myosin heavy-chain promoter. We wanted to address whether this overexpression would protect the heart against paradigmatic stressors. To this end, we studied isolated atrial preparations in an organ bath under normoxic and hypoxic conditions and after prolonged exposure to high histamine concentrations. Moreover, we assessed cardiac function using echocardiography in mice with cardiac hypertrophy due to overexpression of the catalytic subunit of PP2A (PP2A-TG) in the heart [H 2 -TG Â PP2A-TG = double transgenic (DT)] or H 2 -TG with cardiac systolic failure due to treatment of mice with lipopolysaccharides (LPSs). Furthermore, the effect of ischemia and reperfusion was studied in isolated perfused hearts (Langendorff mode) of H 2 -TG. We detected evidence for the protective role of the overexpressed H 2 -histamine receptors in the contractile dysfunction of DT and isolated atrial preparations subjected to hypoxia. In contrast, we noted the detrimental role of H 2 -histamine receptor overexpression against ischemia (Langendorff perfusion) and LPS-induced systolic heart failure. Hence, the role of H 2 -histamine receptors in the heart is context-sensitive: the results differ between hypoxia (in atrium) and ischemia (perfused whole heart), as well as between genetically induced hypertrophy (DT) and toxin-induced heart failure (LPS). The underlying molecular mechanisms for the protective or detrimental roles of H 2 -histamine receptor overexpression in the mammalian heart remain to be elucidated. SIGNIFICANCE STATEMENTThe beneficial and detrimental effects of the cardiac effects of H 2 -histamine receptors in the heart under stressful conditions, here intended to mimic clinical situations, were studied. The data suggest that depending on the clinically underlying cardiac pathophysiological mechanisms, H 2 -histamine agonists or H 2histamine antagonists might merit further research efforts to improve clinical drug therapy.

“…Such a drug is in principle available with okadaic acid: at 10 nM, it inhibits only PP2A not PP1 [4]. Regrettably, its action is not restricted to the myocardium, and we have shown that, by inhibition of smooth muscle phosphatases, it leads to vasoconstriction in isolated human coronary arteries which would worsen cardiac function [57]. We speculate here that the search for cardiac muscle specific inhibitors of PP2A might be reasonable for the pharmacological treatment of the aging human heart.…”

Section: Discussionmentioning

confidence: 99%

Age-Dependent Protein Expression of Serine/Threonine Phosphatases and Their Inhibitors in the Human Cardiac Atrium

Trapp

Bushnaq

et al. 2019

Advances in Medicine

Heart failure and aging of the heart show many similarities regarding hemodynamic and biochemical parameters. There is evidence that heart failure in experimental animals and humans is accompanied and possibly exacerbated by increased activity of protein phosphatase (PP) 1 and/or 2A. Here, we wanted to study the age-dependent protein expression of major members of the protein phosphatase family in human hearts. Right atrial samples were obtained during bypass surgery. Patients (n=60) were suffering from chronic coronary artery disease (CCS 2-3; New York Heart Association (NYHA) stage 1–3). Age ranged from 48 to 84 years (median 69). All patients included in the study were given β-adrenoceptor blockers. Other medications included angiotensin-converting enzyme (ACE) or angiotensin-receptor-1 (AT1) inhibitors, statins, nitrates, and acetylsalicylic acid (ASS). 100 µg of right atrial homogenates was used for western blotting. Antibodies against catalytic subunits (and their major regulatory proteins) of all presently known cardiac serine/threonine phosphatases were used for antigen detection. In detail, we studied the expression of the catalytic subunit of PP1 (PP1c); I1PP1 and I2PP1, proteins that can inhibit the activity of PP1c; the catalytic subunit of PP2A (PP2Ac); regulatory A-subunit of PP2A (PP2AA); regulatory B56α-subunit of PP2A (PP2AB); I1PP2A and I2PP2A, inhibitory subunits of PP2A; catalytic and regulatory subunits of calcineurin: PP2BA and PP2BB; PP2C; PP5; and PP6. All data were obtained within the linear range of the assay. There was a significant decline in PP2Ac and I2PP2A expression in older patients, whereas all other parameters remained unchanged with age. It remains to be elucidated whether the decrease in the protein expression of I2PP2A might elevate cardiac PP2A activity in a detrimental way or is overcome by a reduced protein expression and thus a reduced activity of PP2Ac.