Primary pulmonary hypertension (PPH) is a fatal disease in which increased pulmonary arterial pressure and vascular resistance lead to right heart failure and death. The cellular mechanisms of PPH remain unclear, the common contention is that the disease may have a variety of different etiological triggers. Vasoconstriction and vascular remodeling both contribute to produce increased pulmonary vascular resistance. A rise in cytosolic free Ca2+ concentration ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) is a trigger for vasoconstriction and a stimulus for cell proliferation (that leads to media hypertrophy and vascular remodeling). [Ca2+]cyt is regulated by membrane potential (Em) because of the voltage-dependence of Ca2+ channels. Em is partially determined by K+ channel activity. Inhibition of K+ channels depolarizes PASMC, opens voltage-dependent Ca2+ channels, and increases [Ca2+]cyt. We recently observed that the mRNA expression of voltage-gated K+ (Kv) channels and the currents through Kv channels (IK(V)) were both significantly attenuated in PASMC from PPH patients, compared with PASMC from normal subjects (organ donors) and patients with non-pulmonary hypertension diseases (NPH) and secondary pulmonary hypertension (SPH). Furthermore, PPH-PASMC had more depolarized Em and higher [Ca2+]cyt than SPH-PASMC. Based on these data, we hypothesize that: PPH originates, in part, from an abnormality in function and expression of Kv channel(s). The resultant decrease of K+ channel activity leads to Em depolarization, [Ca2+]cyt elevation, and thus excessive pulmonary vasoconstriction and persistent PASMC proliferation. Prostacyclin (PGI2) and nitric oxide (NO) exert their vasodilator effects, in part, by stimulating K+ channel transcription, increasing K+ channel activity, and decreasing [Ca2+]cyt.
Four Specific Aims are addressed to test the hypotheses: 1) to characterize IK(V), and to identify the Kv channels that contribute to native IK(V) and are responsible for regulating Em and [Ca2+]cyt in normal PASMC; 2) to compare IK(V), and to determine the qualitative and quantitative differences of Kv channel expression, in PASMC from normal subjects and patients with NPH, SPH and PPH; 3) to characterize and compare the temporal and spatial regulation of [Ca2+]cyt in PASMC from normal subjects and patients with NPH, SPH and PPH; and 4) to investigate the effects of PGI2 and NO on function and expression of K+ channels, and regulation of Em and [Ca2+]cyt. Although SPH and PPH share many clinical characteristics, their etiological mechanisms may be disparate. To search for the defects that are unique to PPH, we will focus on comparing function and expression of Kv channels, and regulation of Em and [Ca2+]cyt between SPH- and PPH-PASMC.
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