Showing papers by "David A. Kass published in 2017"

Nanodomain Regulation of Cardiac Cyclic Nucleotide Signaling by Phosphodiesterases

Abstract: Cyclic nucleotide phosphodiesterases (PDEs) form an 11-member superfamily comprising 100 different isoforms that regulate the second messengers cyclic adenosine or guanosine 3′,5′-monophosphate (cAMP or cGMP). These PDE isoforms differ with respect to substrate selectivity and their localized control of cAMP and cGMP within nanodomains that target specific cellular pools and synthesis pathways for the cyclic nucleotides. Seven PDE family members are physiologically relevant to regulating cardiac function, disease remodeling of the heart, or both: PDE1 and PDE2, both dual-substrate (cAMP and cGMP) esterases; PDE3, PDE4, and PDE8, which principally hydrolyze cAMP; and PDE5A and PDE9A, which target cGMP. New insights regarding the different roles of PDEs in health and disease and their local signaling control are broadening the potential therapeutic utility for PDE-selective inhibitors. In this review, we discuss these PDEs, focusing on the different mechanisms by which they control cardiac function in healt...

Nonmyocyte ERK1/2 signaling contributes to load-induced cardiomyopathy in Marfan mice

Abstract: Among children with the most severe presentation of Marfan syndrome (MFS), an inherited disorder of connective tissue caused by a deficiency of extracellular fibrillin-1, heart failure is the leading cause of death. Here, we show that, while MFS mice (Fbn1C1039G/+ mice) typically have normal cardiac function, pressure overload (PO) induces an acute and severe dilated cardiomyopathy in association with fibrosis and myocyte enlargement. Failing MFS hearts show high expression of TGF-β ligands, with increased TGF-β signaling in both nonmyocytes and myocytes; pathologic ERK activation is restricted to the nonmyocyte compartment. Informatively, TGF-β, angiotensin II type 1 receptor (AT1R), or ERK antagonism (with neutralizing antibody, losartan, or MEK inhibitor, respectively) prevents load-induced cardiac decompensation in MFS mice, despite persistent PO. In situ analyses revealed an unanticipated axis of activation in nonmyocytes, with AT1R-dependent ERK activation driving TGF-β ligand expression that culminates in both autocrine and paracrine overdrive of TGF-β signaling. The full compensation seen in wild-type mice exposed to mild PO correlates with enhanced deposition of extracellular fibrillin-1. Taken together, these data suggest that fibrillin-1 contributes to cardiac reserve in the face of hemodynamic stress, critically implicate nonmyocytes in disease pathogenesis, and validate ERK as a therapeutic target in MFS-related cardiac decompensation.

Transient receptor potential channel 6 regulates abnormal cardiac S-nitrosylation in Duchenne muscular dystrophy.

Abstract: Duchenne muscular dystrophy (DMD) is an X-linked disorder with dystrophin loss that results in skeletal and cardiac muscle weakening and early death. Loss of the dystrophin-sarcoglycan complex delocalizes nitric oxide synthase (NOS) to alter its signaling, and augments mechanosensitive intracellular Ca2+ influx. The latter has been coupled to hyperactivation of the nonselective cation channel, transient receptor potential canonical channel 6 (Trpc6), in isolated myocytes. As Ca2+ also activates NOS, we hypothesized that Trpc6 would help to mediate nitric oxide (NO) dysregulation and that this would be manifest in increased myocardial S-nitrosylation, a posttranslational modification increasingly implicated in neurodegenerative, inflammatory, and muscle disease. Using a recently developed dual-labeling proteomic strategy, we identified 1,276 S-nitrosylated cysteine residues [S-nitrosothiol (SNO)] on 491 proteins in resting hearts from a mouse model of DMD (dmdmdx:utrn+/-). These largely consisted of mitochondrial proteins, metabolic regulators, and sarcomeric proteins, with 80% of them also modified in wild type (WT). S-nitrosylation levels, however, were increased in DMD. Genetic deletion of Trpc6 in this model (dmdmdx:utrn+/-:trpc6-/-) reversed ∼70% of these changes. Trpc6 deletion also ameliorated left ventricular dilation, improved cardiac function, and tended to reduce fibrosis. Furthermore, under catecholamine stimulation, which also increases NO synthesis and intracellular Ca2+ along with cardiac workload, the hypernitrosylated state remained as it did at baseline. However, the impact of Trpc6 deletion on the SNO proteome became less marked. These findings reveal a role for Trpc6-mediated hypernitrosylation in dmdmdx:utrn+/- mice and support accumulating evidence that implicates nitrosative stress in cardiac and muscle disease.

Why publish in the American Journal of Physiology-Heart and Circulatory Physiology?

Abstract: for senior cardiovascular scientists, it is well known and accepted that the American Journal of Physiology ( AJP ) -Heart and Circulatory Physiology publishes important and long-lasting cardiovascular science ([2][1]). Early career investigators and trainees may be less familiar with the history of

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

Abstract: s from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications Bamberg, Germany. 23-25 June, 2017 Published: 10 October 2017 A1 Characterization and development of next-generation sGC stimulators G. Todd Milne (tmilne@ironwoodpharma.com), on behalf of the Ironwood team Ironwood Pharmaceuticals, Cambridge, MA 02142, USA BMC Pharmacology and Toxicology 2017, 18(Suppl 1):A1 The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signalling pathway plays a fundamental role in modulating diverse physiological processes including blood flow, fibrosis, inflammation, and metabolism. sGC stimulators are small-molecule, heme-dependent agonists of sGC that synergize with and enhance endogenous NO signaling. As such, sGC stimulators may provide therapeutic benefits both in diseases associated with impaired NO signaling and in diseases where stimulation of this pathway will restore functional homeostasis. Data from our recent preclinical studies add to the growing body of evidence that sGC stimulators have direct effects on systemic and vascular inflammation, fibrosis, and metabolism. Ironwood is developing IW-1973 and IW-1701 as oral, once-daily sGC stimulators for both cardiovascular and non-cardiovascular systemic disease indications. Phase 1 studies in healthy human subjects demonstrated clear evidence of target engagement, attractive pharmacokinetic properties, and predicted hemodynamic effects, at well-tolerated doses. Phase 2 studies are currently ongoing in patients with achalasia, an esophageal motility disorder, and in patients with diabetes and hypertension. Preclinical characterization of IW-1973 and IW-1701 support the broad therapeutic potential and multi-faceted pharmacology of these compounds. Based on preclinical studies, IW-1973 has extensive distribution into organs including liver, heart, kidney, and lung, which may maximize effects on target organs while limiting systemic hemodynamic effects. The pharmacokinetic profile of IW-1701 has a narrow peak-to-trough ratio, which may provide more consistent pharmacological effect throughout the dosing interval. Ironwood is also developing IW-6463, a novel, CNS-penetrant sGC stimulator that shows target engagement and effects on regional blood flow in the brain. Preclinical data suggest that IW-6463 may be useful in treating CNS disorders including vascular dementia and Alzheimer’s disease. We believe that sGC stimulation, alone or in combination with other mechanisms, may afford therapeutic benefit in multiple diseases. Furthermore, there may be an opportunity to provide targeted treatments by selecting compounds that are well-suited for specific diseases based on pharmacological profile, tissue distribution, pharmacokinetics, and route of administration. © The Author(s). 2017 Open Access This artic International License (http://creativecommons reproduction in any medium, provided you g the Creative Commons license, and indicate if (http://creativecommons.org/publicdomain/ze Competing interest Todd Milne and Ironwood team are employees and shareholders of Ironwood Pharmaceuticals and are developing sGC stimulators for therapeutic

Heart Failure-Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo.

Abstract: Background: In human heart failure, Ser199 (equivalent to Ser200 in mouse) of cTnI (cardiac troponin I) is significantly hyperphosphorylated, and in vitro studies suggest that it enhances myofilament calcium sensitivity and alters calpain-mediated cTnI proteolysis. However, how its hyperphosphorylation affects cardiac function in vivo remains unknown. Methods and Results: To address the question, 2 transgenic mouse models were generated: a phospho-mimetic cTnIS200D and a phospho-silenced cTnIS200A, each driven by the cardiomyocyte-specific α-myosin heavy chain promoter. Cardiac structure assessed by echocardiography and histology was normal in both transgenic models compared with littermate controls (n=5). Baseline in vivo hemodynamics and isolated muscle studies showed that cTnIS200D significantly prolonged relaxation and lowered left ventricular peak filling rate, whereas ejection fraction and force development were normal (n=5). However, with increased heart rate or β-adrenergic stimulation, cTnIS200D mice had less enhanced ejection fraction or force development versus controls, whereas relaxation improved similarly to controls (n=5). By contrast, cTnIS200A was functionally normal both at baseline and under the physiological stresses. To test whether either mutation impacted cardiac response to ischemic stress, isolated hearts were subjected to ischemia/reperfusion. cTnIS200D were protected, recovering 88±8% of contractile function versus 35±15% in littermate controls and 28±8% in cTnIS200A (n=5). This was associated with less cTnI proteolysis in cTnIS200D hearts. Conclusions: Hyperphosphorylation of this serine in cTnI C terminus impacts heart function by depressing diastolic function at baseline and limiting systolic reserve under physiological stresses. However, paradoxically, it preserves heart function after ischemia/reperfusion injury, potentially by decreasing proteolysis of cTnI.

Inorganic Nitrates: Qi for Heart Failure With Preserved Ejection Fraction?

Abstract: In 1847, the chemist Ascanio Sobrero announced a way to make highly explosive compounds. Among them was nitroglycerin, which he made by heating cellulose in the presence of nitric acid to generate a substance he noted resembled light-yellow olive oil (he was Italian after all). Alfred Nobel subsequently figured out how to stabilize the explosive part, ultimately developing dynamite. This made him rich but reportedly also contrite over the impact his invention had on military operations, leading to his creating the Nobel Prizes as a sort of societal payback. Meanwhile, a Scottish physician, T. Lauder Brunton, was using amyl nitrite to treat angina, and when it was later realized that men with coronary disease working in nitroglycerin and dynamite factories had fewer angina episodes while at work but more over the weekend, its clinical use took off.1 Nitroglycerin is still widely used to treat angina and organo-nitrates, such as isosorbide di-nitrate, and its active metabolite isosorbide mononitrate (ISMN) with longer half-lives are also in clinical use. Article, see p 1151 This is recent history compared with what the Chinese uncovered more than a millennium earlier. They found medicinal value in salpeter (KNO3), an inorganic salt that dissociates in aqueous solution into nitrate anion. As explained in a text attributed to the fifth to sixth century Daoist alchemist and physician Tao Hongjing (Figure), the powder placed under the tongue caused heart qi (figuratively life force) to flow freely and treat chest pain and other conditions of cardiovascular distress.2 In addition to its medical and explosive utility, salpeter was used by the middle ages as a food preservative. The element shared by organo-nitrates, such as nitroglycerin and inorganic KNO3−, is nitrate (NO3−). Nitrate itself has no physiological effects, but must undergo a 3-electron reduction …

From Heaven to Heart: Nitroxyl (HNO) in the Cardiovascular System and Beyond

Abstract: Reactions based on the transfer of one or more electrons from a donor (reductant) to an acceptor (oxidant) are at the basis of several physiologically relevant cellular processes. Both reactive oxygen and nitrogen species (ROS and RNS, respectively) can signal through these reduction/oxidation (redox) reactions, particularly via reversible interaction with highly reactive thiols. Nitroxyl (HNO), the one-electron reduction product of nitric oxide (NO•), is an RNS that in the last few lusters has garnered a lot of attention owing to its pharmacological properties that are quite dissimilar from those exhibited by its sibling NO• or other RNS such as nitrite/nitrate. HNO uniqueness becomes particularly evident in the cardiovascular system. One aim of this chapter is to put the following three fundamental chemical properties of HNO in a cardiovascular physiology and therapeutic perspective: (1) HNO elective, and likely selective thiophilic nature; (2) inertness toward ROS; and (3) modest reactivity with molecular O 2 . With this conceptual framework in mind, here we will first review routes accounting for possible HNO endogenous formation as they may be relevant to govern basal and stress-stimulated cardiac and vascular function. Then, we will provide an updated account of the pharmacological properties of HNO donors in the heart and in vessels, both in vivo and in vitro, under normal and disease conditions, flanking this evidence with additional HNO pharmacological properties that may nicely complement its main cardiovascular actions. We will conclude discussing the perspective of HNO donors as a treatment for heart failure, more specifically for acute decompensated heart failure (ADHF), comparing HNO therapeutic portfolio to current mainstay ADHF therapies.

Why publish in the

Abstract: (Why publish?). This paper forwards an opinion about authors’ and journals’ motivations for scientific writing. Personal and institutional motivations are listed and discussed and, in regard to biodiversity sciences, I propose that a nationalistic motivation is also pertinent in a biodiversity-rich country such as Brazil. Curiosity and competitiveness should be combined for better results. Finally I discuss ground-breaking science within a post-modern perspective, and how the mere act of scientific writing might trigger both scientific and social revolutions.

Cyclic GMP/Protein Kinase Localized Signaling and Disease Implications

Abstract: Cyclic guanosine 3′,5′-monophosphate (cGMP) and its downstream target, protein kinase G (PKG or cGK), play central roles in cellular regulation and are important to cardiovascular homeostasis and disease pathophysiology. Cyclic GMP is synthesized via either nitric oxide (NO) or natriuretic peptide (NP) stimulation pathways, each coupled to corresponding cyclases, and catabolized by select members of the phosphodiesterase superfamily. Growing evidence now supports control of cGMP and PKG in distinct microdomains within the myocyte, which results in differential downstream targeting. This regional control stems from distinct localization of the relevant signaling components and their capacity to translocate in the cell under both physiological and pathophysiological conditions to further impact the net response. This chapter discusses current understanding of microdomain regulation of the cGMP/PKG pathway, as this information is important to optimally leverage their effects for the treatment of cardiovascular disease.