Abstract 15054: IP3 Receptor Modulates Maladaptive Vascular Responses in Heart Failure
Introduction: Patients with heart failure (HF) have augmented vascular tone which increases cardiac workload, impairing cardiac output and adversely affecting outcomes. However, the molecular mechanisms underlying the maladaptive vascular responses observed in HF are not fully understood.
Hypothesis: The type 1 inositol 1,4,5-trisphosphate receptor (IP3R1), an intracellular Ca2+ release channel located in vascular smooth muscle cells (VSMC), plays a key role in regulating vascular tone in HF.
Methods/Results: We generated VSMC-specific IP3R1 KO mice (cre/flox recombinant technique), which displayed blunted responses to angiotensin II (ATII) and phenylephrine (PE), both in vivo (acute responses measured by Millar catheter, chronic responses assessed by radiotelemetry) and ex vivo (in aortic and mesenteric segments). To evaluate vascular responses in failing hearts, we used different models of HF: the ischemic model (coronary artery ligation) and the pressure overload (thoracic aortic constriction, TAC). In both models the VSMC-KO mice exhibited a significantly attenuated progression towards decompensated HF (assessed via echocardiography), with decreased afterload (measured via hemodynamic pressure-volume loops), and attenuation of interstitial cardiac fibrosis, alongside with a markedly improved coronary perfusion. Notably, there were no differences in the activation of the adrenergic and the renin-angiotensin-aldosterone system. In vitro, we determined that VSMC isolated from KO mice displayed significantly blunted Ca2+ responses to PE and ATII compared with flox littermates, whereas no difference was detected when incubating with IP3R inhibitors (xestospongin C or 2-aminoethoxydiphenyl borate). These results were confirmed in denuded mesenteric arteries preparations. Mechanistically, we established that in HF there is an activation of myosin light chain kinase (MLCK) in VSMC, which is markedly blunted in KO mice.
Conclusions: Taken together, our data indicate for the first time that antagonism of the IP3R1 system may be of benefit in reversing increased vascular tone in patients with HF. Vascular IP3R1 may thereby represent an important, novel target for therapeutic blockade in the pharmacological treatment of HF.
Author Disclosures: G. Santulli: None. S.R. Reiken: None. Q. Yuan: None. A. Marks: None.
- © 2016 by American Heart Association, Inc.