TARGETING PROTEIN KINASE G TO TREAT CARDIAC PROTEOTOXICITY
Impaired or insufficient protein kinase G (PKG) signaling and protein quality control (PQC) are hallmarks of most forms of cardiac disease, including heart failure. Their dysregulation has been shown to contribute to and exacerbate cardiac hypertrophy and remodeling, reduced cell survival and disease pathogenesis. Enhancement of PKG signaling and PQC are associated with improved cardiac function and survival in many pre-clinical models of heart disease. While many clinically used pharmacological approaches exist to stimulate PKG, there are no FDA-approved therapies to safely enhance cardiomyocyte PQC. The latter is predominantly due to our lack of knowledge and identification of proteins regulating cardiomyocyte PQC. Recently, multiple studies have demonstrated that PKG regulates PQC in the heart, both during physiological and pathological states. These studies tested already FDA-approved pharmacological therapies to activate PKG, which enhanced cardiomyocyte PQC and alleviated cardiac disease. This review examines the roles of PKG and PQC during disease pathogenesis and summarizes the experimental and clinical data supporting the utility of stimulating PKG to target cardiac proteotoxicity.
PKG1Α CYSTEINE-42 REDOX STATE CONTROLS MTORC1 ACTIVATION IN PATHOLOGICAL CARDIAC HYPERTROPHY
Stimulated PKG1α (protein kinase G-1α) phosphorylates TSC2 (tuberous sclerosis complex 2) at serine 1365, potently suppressing mTORC1 (mechanistic [mammalian] target of rapamycin complex 1) activation by neurohormonal and hemodynamic stress. This reduces pathological hypertrophy and dysfunction and increases autophagy. PKG1α oxidation at cysteine-42 is also induced by these stressors, which blunts its cardioprotective effects.
Oxidation of PKG1α at C42 reduces its phosphorylation of TSC2, resulting in amplified PO-stimulated mTORC1 activity and associated hypertrophy, dysfunction, and depressed autophagy. This is ameliorated by direct GC-1 stimulation.
ENDOMYOCARDIAL BIOPSY CHARACTERIZATION OF HEART FAILURE WITH PRESERVED EJECTION FRACTION AND PREVALENCE OF CARDIAC AMYLOIDOSIS
July 2020 JACC Heart Failure
Objectives: This study prospectively evaluated endomyocardial biopsies in patients with heart failure with preserved ejection fraction (HFpEF) to identify histopathologic phenotypes and their association with clinical characteristics.
Background: Myocardial tissue analysis from a prospectively defined HFpEF cohort reflecting contemporary comorbidities is lacking.
Methods: Patients with HFpEF (EF ≥50%) referred to the Johns Hopkins HFpEF Clinic between August 2014 and September 2018 were enrolled for right heart catheterization and endomyocardial biopsy. Clinical features, echocardiography, hemodynamics, and tissue histology were determined and compared with controls (unused donor hearts) and HF with reduced EF (HFrEF).
Conclusions: In this large, prospective myocardial tissue analysis of HFpEF, myocardial fibrosis and hypertrophy were common, CD68+ inflammation was increased, and CA prevalence was 14%. Tissue analysis in HFpEF might improve precision therapies by identifying relevant myocardial mechanisms.
OBESITY COULD SHIFT SEVERE COVID-19 DISEASE TO YOUNGER AGES
May 2020 Lancet
Populations with a high prevalence of obesity, COVID-19 will affect younger populations more than previously reported. Public messaging to younger adults, reducing the threshold for virus testing in obese individuals, and maintaining greater vigilance for this at-risk population should reduce the prevalence of severe COVID-19 disease.
LEVERAGING SIGNALING PATHWAYS TO TREAT HEART FAILURE WITH REDUCED EJECTION FRACTION.
May 2019 Circ Res
Advances in the treatment of heart failure with reduced ejection fraction due to systolic dysfunction are engaging an ever-expanding compendium of molecular signaling targets. This review explores therapies that have proven successful, those that have not, those that are moving into the clinic but whose utility remains to be confirmed, and those that remain in the experimental realm.
IN VIVO SELECTIVE INHIBITION OF TRPC6 BY ANTAGONIST BI 749327 AMELIORATES FIBROSIS AND DYSFUNCTION IN CARDIAC AND RENAL DISEASE
April 2019 PNAS
New TRPC6 inhibitor tested in mouse models of heart and kidney disease
PKG1-MODIFIED TSC2 REGULATES MTORC1 ACTIVITY TO COUNTER ADVERSE CARDIAC STRESS
January 2019 Nature
How Viagra Puts A Brake on A Master Growth Regulator to Treat Heart Disease
CHRONIC ATRIAL AND VENTRICULAR PACING IN THE MOUSE
February 2019 Circ Heart Fail
The new method to chronically pace conscious mice yields stable atrial and ventricular capture and a means to dissect basic mechanisms of electromechanical physiology and therapy.
MARKED DISPARITY OF MICRORNA MODULATION BY CGMP-SELECTIVE PDE5 VERSUS PDE9 INHIBITORS IN HEART DISEASE
August 2018 JCI Insight
Seemingly similar therapeutic interventions can be barcoded by profound differences in miR signatures, and reversing disease-associated miR changes is not required for therapy success.
ACUTE ENHANCEMENT OF CARDIAC FUNCTION BY PHOSPHODIESTERASE TYPE 1 INHIBITION
October 2018 Circulation
Blocking PDE1 improves short-term heart function
TRANSIENT RECEPTOR POTENTIAL CHANNEL 6 REGULATES ABNORMAL CARDIAC S-NITROSYLATION IN DUCHENNE MUSCULAR DYSTROPHY
December 2017 PNAS
These findings reveal a role for Trpc6-mediated hypernitrosylation in Duchenne muscular dystrophy and support accumulating evidence that implicates nitrosative stress in cardiac and muscle disease.
NEONATAL TRANSPLANTATION CONFERS MATURATION OF PSC-DERIVED CARDIOMYOCYTES CONDUCIVE TO MODELING CARDIOMYOPATHY
January 2017 Cell Rep
Pluripotent stem cells (PSCs) offer unprecedented opportunities for disease modeling and personalized medicine. This study lays a foundation for understanding human CM maturation and pathogenesis and can be instrumental in PSC-based modeling of adult heart diseases.
TETRAHYDROBIOPTERIN PROTECTS AGAINST HYPERTROPHIC HEART DISEASE INDEPENDENT OF MYOCARDIAL NITRIC OXIDE SYNTHASE COUPLING
March 2016 J Am Heart Assoc
Nitric oxide synthase uncoupling occurs under conditions of oxidative stress modifying the enzyme's function so it generates superoxide rather than nitric oxide. BH4 protection against adverse remodeling in hypertrophic cardiac disease is not driven by its prevention of myocardial nitric oxide synthase uncoupling, as presumed previously. Instead, benefits from exogenous BH4 are mediated by a protective effect coupled to suppression of inflammatory pathways and myocardial macrophage infiltration.
PACEMAKER-INDUCED TRANSIENT ASYNCHRONY SUPPRESSES HEART FAILURE PROGRESSION.
Dec 2015 Sci Transl Med
Uncoordinated contraction from electromechanical delay worsens heart failure pathophysiology and prognosis, but restoring coordination with biventricular pacing, known as cardiac resynchronization therapy (CRT), improves both. Results suggest that PITA could bring the benefits of CRT to the many heart failure patients with synchronous contraction who are not CRT candidates.
DUAL LABELING BIOTIN SWITCH ASSAY TO REDUCE BIAS DERIVED FROM DIFFERENT CYSTEINE SUBPOPULATIONS: A METHOD TO MAXIMIZE S-NITROSYLATION DETECTION
January 25, 2025
S-nitrosylation (SNO), an oxidative post-translational modification of cysteine residues, responds to changes in the cardiac redox-environment. Using a protocol comprising 2 tags for dual-labeling maximizes overall detection of SNO by reducing the previously unrecognized labeling bias derived from different cysteine subpopulations.
PREVENTION OF PKG1Α OXIDATION AUGMENTS CARDIOPROTECTION IN THE STRESSED HEART
June 2015 JCI
The cGMP-dependent protein kinase-1α (PKG1α) transduces NO and natriuretic peptide signaling; therefore, PKG1α activation can benefit the failing heart. These results demonstrate that myocardial PKG1α oxidation prevents a beneficial response to pathological stress, may explain variable responses to PKG1α pathway stimulation in heart disease, and indicate that maintaining PKG1α in its reduced form may optimize its intrinsic cardioprotective properties.
PHOSPHODIESTERASE 9A CONTROLS NITRIC-OXIDE-INDEPENDENT CGMP AND HYPERTROPHIC HEART DISEASE
March 2015 Nature
Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.
SOLUBLE GUANYLATE CYCLASE IS REQUIRED FOR SYSTEMIC VASODILATION BUT NOT POSITIVE INOTROPY INDUCED BY NITROXYL IN THE MOUSE
February 2015 Hypertension
Nitroxyl (HNO), the reduced and protonated form of nitric oxide (NO·), confers unique physiological effects including vasorelaxation and enhanced cardiac contractility. sGC and cGMP-dependent signaling are necessary and sufficient for HNO-induced vasodilation in vivo but are not required for positive inotropic action. Redox modulation of protein kinase G-1α is not a mechanism for HNO-mediated vasodilation.