Old dog, new tricks: novel cardiac targets and stress regulation by protein kinase G.
The second messenger cyclic guanosine 3'5' monophosphate (cGMP) and its downstream effector protein kinase G (PKG) have been discovered more than 40 years ago. In vessels, PKG1 induces smooth muscle relaxation in response to nitric oxide signalling and thus lowers systemic and pulmonary blood pressure. In platelets, PKG1 stimulation by cGMP inhibits activation and aggregation, and in experimental models of heart failure (HF), PKG1 activation by inhibiting cGMP degradation is protective. The net effect of the above-mentioned signalling is cardiovascular protection. Yet, while modulation of cGMP-PKG has entered clinical practice for treating pulmonary hypertension or erectile dysfunction, translation of promising studies in experimental HF to clinical success has failed thus far. With the advent of new technologies, novel mechanisms of PKG regulation, including mechanosensing, redox regulation, protein quality control, and cGMP degradation, have been discovered. These novel, non-canonical roles of PKG1 may help understand why clinical translation has disappointed thus far. Addressing them appears to be a requisite for future, successful translation of experimental studies to the clinical arena.
Division of Cardiology, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria herzforschung@gmail.com.
Peter P
PP
Rainer
Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
David A
DA
Kass
D000818:Animals; D002317:Cardiovascular Agents / Q000627:therapeutic use; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006331:Heart Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D058990:Molecular Targeted Therapy; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010084:Oxidation-Reduction; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D015398:Signal Transduction; D013312:Stress, Physiological; D050052:TRPC Cation Channels / Q000378:metabolism
D002317:Cardiovascular Agents; D058986:Phosphodiesterase 5 Inhibitors; D047428:Protein Kinase Inhibitors; D050052:TRPC Cation Channels; D017869:Cyclic GMP-Dependent Protein Kinases; D046988:Proteasome Endopeptidase Complex; D006152:Cyclic GMP
Cardiac mechanosensing; Phosphodiesterase; Proteasome; Protein kinase G; Redox regulation; cGMP-dependent protein kinase type 1