In patients with heart failure, vasoconstriction of small resistance vessels, especially nonessential circulations becomes excessive in order to maintain blood pressure. As the heart failure syndrome progresses elevated vascular tone becomes maladaptive, increasing cardiac workload and reducing myocardial perfusion. Reducing this excessive vascular tone is an important therapeutic approach for heart failure, but in many cases the drugs, which do not directly target the molecules responsible for the dysfunction, have side-effects and/or lack efficacy. An unappreciated contributor to the increased vasoconstriction in heart failure is the intrinsic dysfunction of vascular smooth muscle cells within resistance vessels. We show that in mice with heart failure, vascular smooth muscle cells have abnormal electrical properties, namely reduced expression and activity of voltage- and Ca2+-activated large conductance K+ (BK) channels and increased depolarization of the membrane potential, leading to increased pressure-induced myogenic vasoconstriction. Conversely, we found that abnormal BK channel function is associated with increased mortality and heart failure after myocardial infarction. We surmise that the role for vasculature BK channels becomes manifest under stress, such as after myocardial infarction or in heart failure. Our goals are to: (a) elucidate the mechanisms underlying the excessive vasoconstriction in heart failure and (b) determine whether limiting vascular smooth muscle depolarization will correct the abnormally increased pressure-induced vasoconstriction and reduce the severity of heart failure and improve survival after myocardial infarction. To limit smooth muscle depolarization, we propose two distinct and novel conceptual approaches of either directly increasing hyperpolarizing currents in vascular smooth muscle using transgenic or pharmacological methods, or indirectly hyperpolarizing vascular smooth muscle cells by increasing endothelial-derived vasodilating autacoids and hyperpolarization events.
Three Aims are proposed: (1) to elucidate the molecular mechanisms mediating heart failure-induced vasoconstriction. (2) To determine whether augmenting the expression and activity of smooth muscle K+ channels can restore normal vascular reactivity and improve cardiac function in mice with systolic heart failure. (3) To test the hypothesis that indirect hyperpolarization of vascular smooth muscle by enhancing small and intermediate conductance Ca2+-dependent K+ currents in endothelial cells can improve survival and heart failure after myocardial infarction in wild-type mice and mice with dysfunctional BK channels. The proposed experiments are designed to identify key molecular mechanisms responsible for the vasculature dysfunction associated with heart failure and new approaches for the treatment of heart failure and myocardial infarction.
An unappreciated contributor to the increased vasoconstriction in heart failure is the intrinsic dysfunction of vascular smooth muscle cells within resistance vessels, caused by the reduced expression and function of potassium ion channels and increased depolarization of the membrane potential. Our proposal focuses on determining whether limiting the depolarization of vascular smooth muscle cells will correct the abnormally increased vasoconstriction and reduce the severity of heart failure in mice after myocardial infarction. These studies may identify a new approach to treat heart failure.
|Katchman, Alexander; Yang, Lin; Zakharov, Sergey I et al. (2017) Proteolytic cleavage and PKA phosphorylation of ?1C subunit are not required for adrenergic regulation of CaV1.2 in the heart. Proc Natl Acad Sci U S A 114:9194-9199|