Adult (3 month) mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an increased cAMP-induced cardiac workload (~30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here, we show classical cardiac hypertrophy markers were absent in TGAC8, and that total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8 was encased by thicker LV walls harboring an increased number of small cardiac myocytes, and a network of small interstitial proliferative non-cardiac myocytes compared to wild type (WT) littermates; Protein synthesis, proteosome activity, and autophagy were enhanced in TGAC8 vs WT, and Nrf-2, Hsp90α, and ACC2 protein levels were increased. Despite increased energy demands in vivo LV ATP and phosphocreatine levels in TGAC8 did not differ from WT. Unbiased omics analyses identified more than 2,000 transcripts and proteins, comprising a broad array of biological processes across multiple cellular compartments, which differed by genotype; compared to WT, in TGAC8 there was a shift from fatty acid oxidation to aerobic glycolysis in the context of increased utilization of the pentose phosphate shunt and nucleotide synthesis. Thus, marked overexpression of AC8 engages complex, coordinate adaptation 'circuity' that has evolved in mammalian cells to defend against stress that threatens health or life (elements of which have already been shown to be central to cardiac ischemic pre-conditioning and exercise endurance cardiac conditioning) that may be of biological significance to allow for proper healing in disease states such as infarction or failure of the heart.
Adult mice with a marked increase in Adenylyl cyclase (AC) activity due to cardio-specific over expression of adenylyl cyclase (AC) type VIII (TGAC8) have an incessantly cardiac work load adapt to this chronic, severe cAMP stress for up to a year without signs of heart failure and without excessive mortality compared to wild-type littermates (WT). Here we focused on mechanisms that underly the TGAC8 adaptive paradigm.Although TGAC8 mice had a 30% increase in both HR and cardiac output, a 23% increase in EF (echocardiography), neither total LV mass nor pathologic hypertrophy biomarkers differed by genotype. Compared to WT the LV cavity volume was reduced in TGAC8, but was encased by thicker LV walls, harboring populations of both smaller cardiac myocytes, and small non-cardiac interstitial cells having increased nuclear EdU labeling. Protein synthesis, proteosome activity, autophagy, Nrf-2 and Hsp90α proteins were also increased in TGAC8 vs WT, but super-oxide radicals did not differ. Despite an apparently marked increased energy demand due to a chronically increased cardiac workload in the context of a chronically increased HR and EF, steady-state LV ATP and phosphocreatine in vivo did not differ in TGAC8 vs WT. Further Acc2, known to suppress fatty acid oxidation and to increase aerobic glycolysis in the context of enhanced utilization of the pentose phosphate shunt, and NADH/NADPH cycling were both elevated in TGAC8 vs WT mice.Unbiased omics unveiled additional genotypic differences in the potential mechanisms involved in the chronically increased TGAC8 heart performance and the adaptive paradigm in response to this chronic stress. 2,323 transcripts and 2,184 proteins, spanning a wide array of biological processes and molecular functions in numerous cellular compartments, including over 250 canonical signaling pathways, that integrate stress responses, cytokine and T cell receptor signaling, immune responses, ROS scavenging, protection from apoptosis, and nutrient sensing, were activated in TGAC8 vs WT. Several adaptive mechanisms that limit cAMP/PKA signaling were also activated in TGAC8.Thus, in addition to markedly increased cardiac work, the chronic, intense AC-PKA-Ca2+ signaling within the adult TGAC8 heart concurrently activates a consilience of adaptive mechanisms within the TGAC8 LV that resemble survival mechanisms within cancer cells.
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