Abstract 2407: Increased Arteriolar Resistance Of Heart Failure Is Associated With Rho-Independent Inhibition Of MLCP.
Background: The clinical syndrome of heart failure (HF) is caused by decreased cardiac output, and is both compensated for and exacerbated by increased systemic vascular resistance (SVR). We posit that a mechanistic understanding of the vasomotor abnormalities that accompany HF may enable new diagnostic and therapeutic tools.
Objective: To determine the molecular mechanisms underlying increased resistance of mesenteric arteries (MAs) in a mouse model of HF.
Methods & Results: In a mouse left anterior descending (LAD)-ligation model of myocardial infarction (MI)-induced HF, echocardiography and hemodynamics documented markedly increased SVR. Isolated perfused MAs manifested dramatic, early (1 wk), and sustained (12 wk) increases in myogenic responses (MR). Vasoconstrictor responses to S1P and ET-1 were also increased in MAs of HF but not SHAM mice. At wk 6, aorta and MA were analyzed for levels and or activity of
Rho/GTP-Rho, a key mediator of enhanced vasoconstrictor responses. We also measured total and phosphorylated levels of:
MYPT1 (Thr850), the myosin targeting subunit of myosin light chain phosphatase (MLCP), an end-regulatory molecule of smooth muscle contraction;
CPI-17 (Thr38), an inhibitor of MLCP; and (iv) myosin light chain itself (MLC; Ser19).
When phosphorylated, MYPT1 inhibits MLCP, limiting its dephosphorylation of MLC, and thus prevents relaxation. Given our results with respect to ET-1 and S1P, we were surprised to find significantly decreased levels of total and GTP-Rho in MAs and aorta of HF as compared to SHAM mice. By contrast, increased levels of phosphorylated-MYPT1, CPI-17 and MLC were found in HF.
Conclusion: These data implicate a heretofore unrecognized mechanism of ‘Rho-independent’ inhibition of MLCP in the increased SVR, MR, and vasoconstrictor responses observed in the MI model of HF in mice.