Pulmonary hypertension (PH) is a disease manifest by increased vascular resistance and pressure in the lungs. The prognosis is poor in that patients untreated for PH often develop heart failure leading to death. The only FDA-approved therapy for PH, infused prostacyclin, is cost prohibitive and cumbersome because an infusion pump has to be implanted. This effort produces only symptomatic relief with no therapy for the underlying cause.
I aim to use adenoviral delivery of adenylyl cyclase type 6 (AC6), an enzyme that generates the second messenger, cAMP, and is the target of key receptors activated to maintain vascular tone, to pulmonary artery smooth muscle cells (PASMC) from patients with and without primary PH to determine the benefit and understand the impact of increased AC expression on vascular cell physiology. I hypothesize that enhanced cAMP production via increased expression of AC6 will regulate ion channel function and restore ion homeostasis in diseased PASMC. I also hypothesize that signaling via G proteins is compartmentalized such that """"""""signaling molecular machines"""""""" exist to impart the differentiated state of pulmonary vascular smooth muscle. Understanding this higher order organization may help define new approaches to achieve the desired therapeutic end point of reduced vascular tone through viral mediated delivery of effector genes such as AC6.
| Patel, Hemal H; Zhang, Shen; Murray, Fiona et al. (2007) Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension. FASEB J 21:2970-9 |
| Patel, Hemal H; Head, Brian P; Petersen, Heidi N et al. (2006) Protection of adult rat cardiac myocytes from ischemic cell death: role of caveolar microdomains and delta-opioid receptors. Am J Physiol Heart Circ Physiol 291:H344-50 |
| Tsutsumi, Yasuo M; Patel, Hemal H; Lai, N Chin et al. (2006) Isoflurane produces sustained cardiac protection after ischemia-reperfusion injury in mice. Anesthesiology 104:495-502 |
| Head, Brian P; Patel, Hemal H; Roth, David M et al. (2005) G-protein-coupled receptor signaling components localize in both sarcolemmal and intracellular caveolin-3-associated microdomains in adult cardiac myocytes. J Biol Chem 280:31036-44 |
