Cyclic GMP-Dependent Protein Kinases and the Cardiovascular System

Abstract

Abstract-Signaling cascades initiated by nitric oxide (NO) and natriuretic peptides (NPs) play an important role in the maintenance of cardiovascular homeostasis. It is currently accepted that many effects of these endogenous signaling molecules are mediated via stimulation of guanylyl cyclases and intracellular production of the second messenger cGMP. Indeed, cGMP-elevating drugs like glyceryl trinitrate have been used for more than 100 years to treat cardiovascular diseases. However, the molecular mechanisms of NO/NP signaling downstream of cGMP are not completely understood. Recent in vitro and in vivo evidence identifies cGMP-dependent protein kinases (cGKs) as major mediators of cGMP signaling in the cardiovascular system. In particular, the analysis of conventional and conditional knockout mice indicates that cGKs are critically involved in regulating vascular remodeling and thrombosis. Key Words: smooth muscle relaxation Ⅲ cGMP Ⅲ nitric oxide Ⅲ atherosclerosis Ⅲ cardiac hypertrophy T he second messenger cyclic guanosine-3Ј,5Ј-monophosphate (cGMP) that was identified almost 40 years ago 1 is generated from GTP either by soluble guanylyl cyclase (sGC) or particulate guanylyl cyclases (pGCs) (Figure 1A). The sGC is activated by nitric oxide (NO) or carbon monoxide, whereas the pGCs bind a family of natriuretic peptides (NPs) consisting of atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP, respectively). 2,3 Cyclic GMP is degraded by cGMP-hydrolyzing phosphodiesterases (PDEs). 4 The vasodilatory effect of NO-generating drugs (eg, glyceryl trinitrate) is used therapeutically in the treatment of angina pectoris and congestive heart failure. A plethora of pharmacological studies as well as the analysis of transgenic mice that overexpress or lack NO synthases (NOS), NPs, or pGCs underscored the importance of NO/NP signaling in the regulation of blood pressure, hemostasis, and cardiac and vascular remodeling. 5 These studies also uncovered a marked complexity of signaling via NO/NPs, for example that NO can both inhibit and promote atherogenesis. The identification of the cellular and molecular mechanisms that mediate Original

Acute effects of 17β-estradiol on myocardial pH, Na+, and Ca2+ and ischemia-reperfusion injury

“…Recent studies in a number of organs are consistent with the postulate that NHE1 may be inhibited by signal transduction pathways associated with increases in NO and specifically the cascade of steps through NO, cGMP, cGMP-dependent kinase (cGK) and p38 MAPK (19). These include studies from isolated hepatocytes that suggest a preconditioning effect limiting increases in [Na ϩ ] i during hypoxia is mediated by NO through cGK and p38 MAPK (11) and furthermore that atrial natriuretic peptide diminishes hypoxia-induced increases in [Na ϩ ] i by a similar pathway that inhibits NHE1 (10).…”

“…Initiation of 40 min of ischemia was designated t ϭ 0 min. 23 Na, 31 P, and 19 F NMR were used to measure Na i ϩ , pHi and high-energy phosphates, and [Ca 2ϩ ]i, respectively. To measure Na i ϩ , 7.5 mmol/l dysprosium triethylenetetraminehexaacetic acid was substituted for NaCl in the perfusate isosmotically, and Ca 2ϩ was added until the perfusate concentration reached 1.8 -2 mmol/l as measured using Ca 2ϩ electrode (31).…”

“…23 Na, 31 P, and 19 F spectra were generated from the summed free induction decays of 1,000, 148, and 1,500 excitation pulses (90°, 60°, and 45°) using 2-, 4-, and 2-kilobyte word data files and Ϯ4,000-, Ϯ4,000-, and Ϯ5,000-Hz sweep widths, respectively. Data files were collected over 5-min intervals, but to improve signal-to-noise ratio for 19 F measurement of [Ca 2ϩ ]i, two 5-min files were added together. Because the NMR signal intensity reflected the average for the interval over which data were collected, data in the figures correspond to the midpoint of the appropriate 5-or 10-min acquisition interval.…”

Translational research of C-type natriuretic peptide (CNP) into skeletal dysplasias

“…The role of other molecules related to the CNP/ GC-B system on endochondral bone growth (Fig. 3) cGMP-dependent protein kinase (cGK) has been identified as a molecule activated downstream of the natriuretic peptide family and guanylyl cyclase system [28]. Mice depleted of one subtype of the cGK gene, cGKII (cGKII-KO mice), exhibit a short stature phenotype secondary to impaired endochondral bone growth [29], similar to that observed in CNP-KO mice [24].…”

The nitric oxide-cGKII system relays death and survival signals during embryonic retinal development via AKT-induced CREB1 activation

“…16 For instance, cGKI or cGKII display pivotal roles in the cardiovascular system. 17 Vascular smooth muscle tonus is regulated by an interaction between cGKIa and myosin phosphatase in the contraction apparatus of smooth muscle cells. 18 Moreover, cGKI and cGKII are expressed in the CNS and regulate important neuronal functions.…”