Gene Expression Profiles of Vascular Smooth Muscle Show Differential Expression of Mitogen-Activated Protein Kinase Pathways during Captopril Therapy of Heart Failure

Abstract

Congestive heart failure (CHF) is characterized by increased vascular tone and an impairment in nitric-oxide-mediated vasodilatation. We have demonstrated that the blunted response to nitric oxide is due, in part, to a reduction in the leucine-zipper-positive isoform of the myosin-targeting subunit (MYPT1) of myosin light-chain phosphatase. Additionally, we have shown that angiotensin-converting enzyme inhibition, but not afterload reduction with prazosin, preserves leucine-zipper-positive MYPT1 isoform expression in vascular smooth muscle cells and normalizes the sensitivity to cGMP-mediated vasodilatation. We therefore hypothesized that in CHF, growth regulators and cytokines downstream of the angiotensin II receptor are involved in modulating gene expression in vascular tissue. Rats were divided into control and captopril-treated groups following left coronary artery ligation. Gene expression profiles in the aorta and portal vein at baseline and 2 and 4 weeks after myocardial infarction (MI) were analyzed using microarray technology and quantitative real-time PCR. After MI, microarray analysis revealed differential mRNA expression of 21 genes in the aorta of captopril-treated rats 2 and 4 weeks after surgery when compared to gene expression profiles at baseline and without captopril therapy. Real-time PCR demonstrated that captopril suppressed the expression of protein kinases in the angiotensin-II-mediated mitogen-activated protein kinase signaling pathway, including Taok1 and Raf1. These data suggest that in CHF, captopril therapy modulates gene expression in vascular smooth muscle, and some of the beneficial effects of ACE inhibition may be due to differential gene expression in the vasculature.

Increased degradation of MYPT1 contributes to the development of tolerance to nitric oxide in porcine pulmonary artery

“…The presence of leucine zipper is required for PKG to activate MLCP, which leads to MLC dephosphorylation and vasodilatation (18,26,45,47). The abundance of MYPT1 (LZϩ) has been shown to be closely correlated to the relaxation mediated by cGMP-elevating agents such as NO (2,22,28,35,49). In our study, protein levels of both total MYPT1 and MYPT1 (LZϩ) were reduced to a similar extent.…”

“…Changes in expression of MYPT1 and MYPT1 (LZϩ) have been implicated in a number of pathophysiological conditions associated with altered vasodilatation to NO and other nitrovasodilators (2,3,21,28,36). In a rat model of congestive heart failure, decreased expression of MYPT1 (LZϩ) was associated with diminished relaxation of aortas to cGMP (21).…”

Losartan Decreases p42/44 MAPK Signaling and Preserves LZ+ MYPT1 Expression

“…Ca 2+ desensitization (MLC 20 dephosphorylation at a constant [Ca 2+ ]) occurs during all types of smooth muscle activation, including those that MYPT1 is not phosphorylated at Thr696 [36], [37], [38], [39]. These results contrast with those for the relationship between LZ+ MYPT1 and sensitivity to cGMP; results consistently demonstrate that LZ+ MYPT1 expression determines the sensitivity to cGMP-mediated vasodilatation [13], [18]–[20], [23], [26].…”

“…Further captopril therapy preserves both normal LZ+ MYPT1 expression and sensitivity to NO mediated vasodilatation [22] as well as suppresses the expression of genes involved in p42/44 MAPK and p38 MAPK signaling [23]. The present study examined whether captopril treatment of heart failure maintains LZ+ MYPT1 expression by decreasing angiotensin II (Ang II) by testing the ability of angiotensin receptor blocker (ARB) therapy to maintain LZ+ MYPT1 expression and decrease the activation of either p42/44 or p38 MAPK.…”

Regulation of heat shock protein 60 and 72 expression in the failing heart

“…HSF-1 is the primary activator of HSPs in response to stress/injury, though there is now some evidence that HSF-2 interacts with HSF-1 in this setting [16]. HSF-1 levels were more than doubled in CHF, as shown in Fig.…”