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Ischemic heart disease (IHD) is a multifaceted pathological manifestation that continues to press an extensive burden on individuals and healthcare resources. The strenuous weight of this disease affects more than 80 million people in the United States, with an annual economic cost of more than 300 billion in healthcare expenses and lost productivity. Understanding the progression of this disease and the underlying regulatory mechanisms is essential for dampening the substantial socio-economic burden it poses by supporting the development of novel therapeutic strategies for afflicted patients. Myocardial perfusion is largely controlled by the microcirculation, consisting of small arteries and arterioles. Under physiological conditions, an increase in myocardial metabolic activity stimulates coronary vasodilation and increased vascular perfusion. However, pathological coronary stenosis of the conduit arteries impairs downstream flow and O 2 delivery that must be compensated by collateral supply from neighboring nonoccluded regions. The ability of the vasculature to dilate in response to a reduction in flow is paramount for improved perfusion from the collateral circulation. Voltage-gated potassium (Kv) channels present as significant end effectors of vasodilation for many signaling axes, including reactive oxygen species, which are reported to be upregulated under ischemic conditions. Using the clinically relevant swine model for the current study, we isolate a reduction in oxygen tension, ex vivo, as a single characteristic of an otherwise complicated disease and test the hypothesis that hypoxic insult impairs Kv7 channel function. Isometric tension wire myography and perforated patch voltage clamp were used to investigate Kv7 channel contribution to H 2 O 2 -mediated vasodilation and Kv channel currents in response to hypoxic insult. Our data reveal that hypoxic conditions impair H 2 O 2 -mediated vasodilation and that this impairment is attributable, at least in part, to a loss of Kv7 channel activation. Further, protein kinases are known to associate with and activate Kv7 channels in other tissue types. Inhibition of protein kinase A (PKA) yields a similar inhibitory response to blockade of Kv7 channels. Taken together, these studies reveal Kv7 channels as potential targets of hypoxic insult, and their reduced contribution may be responsible for impaired vasoreactivity in the coronary microcirculation in response to hypoxic insult. Funding: NIH RO1 HL139903. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Self et al. (Wed,) studied this question.