Review articleUnanticipated signaling events associated with cardiac adenylyl cyclase gene transfer
Research Highlights
► AC6 expression reduces of hypertrophy, increased cell survival, and improved calcium handling - effects that appear to be cAMP-independent. ► Unlike endogenous transgene AC6 is widely distributed in the cell, enabling interactions with previously inaccessible proteins. ► The beneficial effects of increased AC6 on cardiac function may reflect its interactions with kinases, phosphatases, and transcription factors.
Introduction
Our purpose is to review a very specific topic: mechanisms for the favorable effects of increased cardiac expression of adenylyl cyclase type 6 (AC6) on normal and failing hearts. Unlike most reviews, where a given topic is studied by many groups of scientists, AC6 and its effects on cardiac function have, for the most part, been published by the laboratory of the authors. Citing so many of our papers was therefore unavoidable. The effect of AC in other cells and organs has been a focus of several recent reviews and original articles. For example, increased AC6 expression in cardiac fibroblasts and other cells [1], [2], [3], [4], [5], regulatory properties of cardiac AC6 and AC5 (the other major AC isoform expressed in cardiac myocytes) [6], [7], [8], AC5 in the heart [9], [10], [11], [12], [13], [14], [15], structure–function relationships of various AC isoforms [16], [17], [18], [19], [20], [21], [22], [23], [24], mechanisms for Ca2+ inhibition and stimulation of AC isoforms [25], [26], [27], [28], [29], and the role of AC isoforms in the brain, with a focus on memory [30], [31], [32].
Section snippets
AC structure and activity
Adenylyl cyclase (AC) is a transmembrane protein in cardiac myocytes and other cells and is the effector molecule for the β-adrenergic receptor (βAR) and other G-protein coupled receptors. AC regulates the conversion of adenosine triphosphate (ATP) to 3’,5’-cyclic adenosine monophosphate (cAMP), thereby, through protein kinase A (PKA), initiating a variety of intracellular signaling cascades that influence heart function. AC isoforms possess the general structure shown in Fig. 1: two
AC6 gene transfer for clinical CHF
Recent studies, which will be reviewed, indicate that increased cardiac AC type 6 (AC6), a dominant AC isoform expressed in mammalian cardiac myocytes [49] has protean beneficial effects on the left ventricle (LV) (Table 1). These include (1) increased survival in mice with cardiomyopathy [50]; (2) increased survival in acute myocardial infarction (MI) [51]; (3) reduced action potential duration [52] and facilitation of atrio-ventricular (AV) conduction [53] associated with reduction of AV
AC content and cAMP generation
Using recombinant adenovirus to increase AC6 expression in neonatal cardiac myocytes, it was found that cells with increased AC6 responded to agonist stimulation with marked increases in cAMP production in proportion to protein expressed: AC protein expression was amplified six-fold and ßAR-stimulated cAMP production was increased seven-fold (vs. Ad5. lacZ control) [58]. Basal cAMP was unchanged by AC6 gene transfer. No changes in ßAR number, or in the expression of Gαs or Gαi2 were found. In
Intracellular distribution of AC6
Adenylyl cyclase is predominantly found in the cell membrane. However, using high-resolution electron microscopy after immunohistochemical staining, endogenous AC was also detected in the sarcoplasmic reticulum (SR), nuclear envelope, and perinuclear region in cardiac myocytes [73]. In nerve cells, endogenous AC is detected in endoplasmic reticulum and within the cytoplasm of terminal endings of nerve fibers [74]. Studies using cardiac myocyte homogenates followed by sucrose gradient
Conclusion
The surprising beneficial effects of increased AC6 expression on cardiac function may reflect the effects of intracellular transgene AC6 and its interactions with key signaling molecules, kinases, phosphatases, and transcription factors. Many of these altered pathways have favorable effects on cardiac function, through abrogation of hypertrophy, increased cell survival, and improved calcium handling—effects that appear to be cAMP-independent. Whether these mechanisms are relevant or attainable
Disclosures
Dr. Hammond is founder of and consultant to Renova Therapeutics, Incorporated.
Acknowledgements
Supported by grants from the NIH (5P01HL066941, HL081741, HL088426-01), the Department of Veterans Affairs (Merit grant) and the American Heart Association (Beginning Grant-In-Aid Awards 0765064Y and 0865147F).
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