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Pulmonary hypertension (PHTN) remains a disease with high morbidity and mortality and no known cure. The World Health Organization has categorized PHTN into 5 clinical classifications that include: 1) Pulmonary artery hypertension, 2) Pulmonary hypertension with left heart disease, 3) Pulmonary hypertension with respiratory disease, 4) Pulmonary hypertension caused by chronic thrombotic/Embolic Disease, and 5) Miscellaneous PHTN.1 Despite the broad and varied nature of these clinical conditions, PHTN presents with similar clinical pathological changes in the lung, including altered vaso-reactivity, endothelial dysfunction, vascular intimal and medial remodeling, activation of inflammatory processes, and platelet activation. If untreated these changes lead to right heart stress, failure, and death.1 At the cellular level, enhanced vasoconstriction, endothelial dysfunction and endothelial cell and vascular smooth muscle cell (VSMC) proliferation are key components of disease progression. This underlying pathology is associated with a plethora of molecular changes such as increased inflammatory cytokine expression and increased levels of oxidative stress, altered NO bioavailability and increased growth factor expression. These molecular changes alter the balance of kinase cascades, cAMP, cGMP and rho that ultimately modulate K+ and Ca2+ channel function and expression, cytoskeletal organization, and cell cycle progression.
Current treatment targets for pulmonary hypertension include Ca2+ channel blockade, selective endothelin ETA receptor and dual endothelin receptor antagonism, prostanoid replacement and phosphodiesterase inhibition.2 These treatments may be applied singularly or in combination to achieve therapeutic goals. Moreover, these therapies have had limited success and are often associated with unwanted side effects including systemic hypotension. The rapid rate of drug discovery for this condition is somewhat reassuring, but finding a single drug therapy that targets the numerous pathological changes in pulmonary hypertension, free of side effects, is less plausible.
Over the past two decades, increasing attention has been given to red wine polyphenol, resveratrol (3,5,4'-trihydroxystilbene), a dietary phytoalexin compound. This is due in part to its cardioprotective, vaso-active and anti-cancer properties. This compound is capable of acting as a pleiotrophic agent in anti-oxidant, anti-inflammatory, anti-proliferative and anti-fibrotic capacities. More recently resveratrol has attracted interest as a novel, therapeutic approach for the prevention and treatment of multiple cardiovascular diseases including atherosclerosis and ischemia/reperfusion injury. Importantly, the multiple actions attributed to resveratrol on the systemic and cardiac vasculature may also target the mediators of pulmonary hypertensive diseases.
In the current issue of Hypertension, Csiszar et al. are the first to demonstrate the remarkable efficacy of resveratrol in preventing the pulmonary and cardiac abnormalities in a rat model of pulmonary hypertension induced by monocrotaline (MCT).3 Monocrotaline is a toxic pyrrolizidine alkaloid, and administration of a small MCT dose or its active metabolite, monocrotaline pyrrole, to rats causes a delayed and progressive lung injury, which is characterized by endothelial cell dysfunction, pulmonary vascular remodeling, pulmonary hypertension, and RV hypertrophy. Treatment with resveratrol (25 mg/kg/day started on the day of MCT administration) prevented these changes. The actions of resveratrol were attributed, in part, to reduced pulmonary VSMC proliferation, increased eNOS and NO bioavailability, reduced oxidative stress, decreased inflammatory cytokine levels and decreased lung leukocyte infiltrate and iNOS levels (Figure 1). At the molecular level, TGF-β and TNF-α levels were normalized, NOX subunits of the NADPH oxidase were reduced and eNOS levels were increased.
Despite the intriguing findings presented in this manuscript, a number of questions remain to be elucidated (Figure 1). For example, how does resveratrol affect ion channels, which are important in pulmonary vascular constriction and vascular smooth muscle cell proliferation? Potential targets are membrane associated ion channels, in particular K+ and Ca2+ channels that play a large role in modulating pulmonary vasomotor tone and pulmonary artery VSMC proliferation in acute and chronic hypoxic states.4 Under chronic hypoxic conditions, voltage-activated K+channels (Kv) and voltage-independent Ca2+ channels modulate the increase in chronic pulmonary vasoconstriction4, whereas the resulting sustained increase in intracellular Ca2+ stimulates pulmonary artery VSMC proliferation.5 The effects of resveratrol on these channels in MCT-induced pulmonary hypertension require further study. Interestingly, one might speculate that changes in channel activity could affect both, PASMC constriction as well as proliferation. Furthermore, resveratrol has also been shown to induce smooth muscle relaxation in a number of human and animal vascular beds.6 In these studies resveratrol was shown to affect large-conductance Ca2+ and voltage-activated K+ channels (BKca). These channels are key regulators of pulmonary arterial tone, and their inhibition has been implicated in the development of pulmonary hypertension.
Resveratrol also antagonizes the activation of a number of molecular pathways that underlie the pro-inflammatory and proliferative responses to MCT. Resveratrol inhibits the activation of CREB, c-jun, AP-1 and NF-kB transcription factors. In particular, down regulation of NF-kB, AP-1 and ERK activity by resveratrol is associated with many of its observed anti-oxidative, anti-inflammatory and anti-proliferative effects. Recent studies have verified a link between resveratrol-mediated NF-kB inhibition and AP-1 inhibition in smooth muscle cells7. NF-kB blockade may be secondary to IkB kinase inhibition, preventing NF-kB translocation to the nucleus. Studies performed by Son et al., independently demonstrated that resveratrol decreased pro-inflammatory cytokine transcriptional profiles via inhibition of NF-kB and AP-1 activity when cells were challenged with TNF-α and lipopolysaccharide, respectively.8 Resveratrol also elicits anti-inflammatory effects by decreasing NF-kB -mediated lung neutrophil infiltration9. Additionally, resveratrol has been shown to dose-dependently arrest aortic VSMC in the G1 phase of the cell cycle.10 Reduced ERK-MAPK signaling is also thought to play a role in decreasing cyclin-dependent kinase levels resulting in a cessation of the cell cycle of VSMC.8, 10 In the present study by Csiszar et al., resveratrol-induced an anti-proliferative response in pulmonary VSMC that was associated with S phase cell-cycle arrest.
Another remaining question is whether resveratrol targets multiple processes independently that contribute to the above findings or whether there is an integral element that accounts for these pleiotrophic actions. It is tempting to speculate that ROS scavenging may be at the center of the diverse actions of resveratrol. Increased oxidant stress plays a major role in vasoconstriction, NO bioavailability, cell proliferation and inflammation in pulmonary endothelial cells and VSMC. In addition to directly scavenging ROS, resveratrol also increases the expression of a number of antioxidant enzymes such as glutathione, peroxidase, catalase, and heme-oxygensase1 in aortic vessels, but these changes have not been documented in the pulmonary vasculature. Further work is needed to dissect out the relative importance of each of these contributing factors.
While MCT treatment is one of several models of pulmonary hypertension, questions remain regarding the efficacy of resveratrol in other models of pulmonary hypertension that encompass more severe pathophysiology or in distinctly different pulmonary hypertension models (i.e., chronic hypoxia exposure, early ductus arteriosus ligation, chronic embolic delivery, and others). Moreover, it is unclear whether resveratrol can reverse or attenuate established PTHN, an important clinical goal. Another area of needed study involves gender differences in pulmonary hypertension as resveratrol exerts antiproliferative effects in aortic VSMC by binding to estrogen receptors11, implying gender specific alterations in activity. Finally, the effects of resveratrol on developmental models of pulmonary hypertension need to be studied since these models demonstrate pathophysiologic differences.
In summary, the authors make a convincing argument for multiple beneficial effects of resveratrol on MCT-induced pulmonary hypertension in adult rats. However, additional preclinical studies followed by clinical trials are needed before resveratrol can be considered the magic bullet for pulmonary hypertension.
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