Mitogen activated protein kinases (MAPK), such as ERK1/2 and p38 MAPK and phosphatidylinositol-3 phosphate kinase (PI-3K) play a major role in the development of cardiac hypertrophy. Recently, we have shown their crucial role in the regulation of the myocardial function through their effects on crucial ion channels. It is the focus of this study to resolve the interaction between these pathways and its implication on the function of the normal and hypertrophied cardiomyocytes. To that end, we created arteriovenous fistula in the adult rat that developed volume-overload eccentric cardiac hypertrophy over a 3-week period. We measured the relative activity of ERK1/2, p38 MAPKs and Akt through western blot analysis and assessed the functional density of the outward rectifier potassium current (IK) using the patch-clamp technique. The results showed a mutual negative autoregulation between ERK1/2 and p38 in normal cardiomyocytes, which disappears during cardiac hypertrophy. In addition, PI-3K seems to assume a greater role in mediating IGF-1 effects on the MAPKs during cardiac hypertrophy. This was also relevant to IK functional density which was reduced by activation of both MAPKs and Akt by angiotensin II (ANG II) and insulin-like growth factor-1 (IGF-1), respectively; however, this reduction was reversed by inhibition of PI-3K alone in hypertrophied myocytes but not in normal ones. This raises an important implication relative to the role of IGF-1-dependent activation of PI-3K, which may translate into a differential prognostic for cardiac hypertrophy among ethnic groups. This is true in African Americans, having higher circulating IGF-1 levels, and especially true for the athletes among them.

Over the past several decades, the rate of pulmonary nontuberculous my- cobacterial (PNTM) disease has been increasing. PNTM patients gener- ally consist of lean and tall women presenting with symptoms in the sixth decade of life. They have a de nitive morphophenotype, but no consistent immunological abnormalities despite extensive investigation. I hypothesized that respiratory epithelial dysfunction might play a critical role in PNTM disease predisposition because diseases with defects of mucociliary transport have high rates of PNTM disease that increase with age, suggesting a direct connection between airway epithelial function and PNTM disease. I found that PNTM patients have a distinct respiratory epithelial phenotype ex vivo and decreased nasal nitric oxide levels in vivo. The PNTM ex vivo phenotype consists of an abnormally low resting ciliary beat frequency (CBF) and abnormal CBF response to toll-like receptor (TLR) agonists. The depressed baseline CBF response in PNTM patient cells can be normalized ex vivo by augmenting the nitric oxide-cyclic guanosine monophosphate pathway without appreciable e ect on CBF in healthy controls. In healthy controls, bacterial TLR agonists increase CBF and viral TLR agonists decrease CBF. In PNTM patients these responses are impaired and are not normalized with the normalization of the resting CBF rate. Inhibitor-induced disruption of signalling pathways associated with CBF regulation demonstrated that the majority of the CBF response to TLR agonists involves the PI-3K pathway and PKC. Inhibition of the PI-3K pathway (PI-3K , Akt1, and PDK1) closely mimicked the ex vivo phenotype seen in PNTM patient respiratory epithelia. These data identify a novel aspect of PNTM disease with in vivo and ex vivo correlates that suggest that PNTM infection is associated with abnormal function at both the CBF and TLR response levels. This phenotype is novel, reproducible, and provide a foundation with which to determine the genetic basis of PNTM infection.