Participation in disease progression
A variety of diseases including stroke, atherosclerosis, diabetes, ischemic heart diseases and neurodegenerative diseases are caused from the disturbances in mitochondrial functions. The production of peroxynitrite occurs either within mitochondria or may achieved from extra mitochondrial compartments. Peroxynitrite inhibits Mn-SOD by nitration (MacMillan-Crow LA and Thompson, 1999) and thus checking the breaking of nearby formed superoxide that further promotes its formation. Peroxynitrite causes toxicity in mitochondria through two mechanisms- either by oxidative reactions directly or by free radical-induced damage involving CO2 that forms CO3− • and NO2• radicals (Radi et al., 2002a, b). This latter …show more content…
It can be subdivided into 4 distinct categories according to its primary pathophysiological mechanism, namely cardiogenic, hypovolemic, obstructive and distributive (Weil and Shubin, 1971). In the first 3 types, perfusion is changed as a consequence of cardiac output decrease, whereas distributive types of shock are related to a primary dysfunction of the resistive component of the cardiovascular system. In vasoplegia, vascular tone is reduced and there is a noticeably depressed constrictive response of arterioles to vasoconstrictors, and is a main cause is septic shock (Levy et al., 2010). Sepsis-induced vasoplegia is a component of a generalized circulatory dysfunction that involves the macro- and microcirculation, heart, and endothelium, as an outcome of a systemic inflammatory response accumulated by the host in response to invading microorganisms (Hollenberg, 2009). Various evidences accumulated over the past 2 decades has suggested that enhanced formation of free radicals and oxidant species symbolizes a key pathophysiological mechanism of cardiovascular dysfunction and organ damage during sepsis (Pacher et al., 2007). Among such oxidizing agents, the powerful oxidant peroxynitrite has received particular interest as an essential mediator …show more content…
Different types of mechanisms have been put forward to explain peroxynitrite-mediated reduction of vascular tone. Bioenergetic failure associated to the direct effects of peroxynitrite on the mitochondrial electron transport chain, or to DNA-damage-mediated activation of PARP with successive reduction in cellular NAD+ and ATP has been suggested as the primary mechanism connecting peroxynitrite generation with vascular contractile dysfunction (Pacher and Szabó, 2008; Esposito and Cuzzocrea, 2009). Therefore, pharmacological inhibition of PARP (Jagtap et al., 2002; Goldfarb et al., 2002) or its genetic deletion (Soriano et al., 2002; Liaudet et al., 2000) have been linked with significant improvements of vascular contractility and reduced hypotension in different animal models of septic and hemorrhagic shock. Other mechanisms include the opening of KATP channels in response to peroxynitrite, causing induction of vascular hyperpolarization (Li et al., 2004; Ohashi et al., 2005), activation of matrix metalloproteinases (especially MMP-2) in the vessel wall by peroxynitrite (Cena et al., 2010) and ultimately impairment of myosin light chain phosphorylation due to myosin phosphatase activation by peroxynitrite leading to
A variety of diseases including stroke, atherosclerosis, diabetes, ischemic heart diseases and neurodegenerative diseases are caused from the disturbances in mitochondrial functions. The production of peroxynitrite occurs either within mitochondria or may achieved from extra mitochondrial compartments. Peroxynitrite inhibits Mn-SOD by nitration (MacMillan-Crow LA and Thompson, 1999) and thus checking the breaking of nearby formed superoxide that further promotes its formation. Peroxynitrite causes toxicity in mitochondria through two mechanisms- either by oxidative reactions directly or by free radical-induced damage involving CO2 that forms CO3− • and NO2• radicals (Radi et al., 2002a, b). This latter …show more content…
It can be subdivided into 4 distinct categories according to its primary pathophysiological mechanism, namely cardiogenic, hypovolemic, obstructive and distributive (Weil and Shubin, 1971). In the first 3 types, perfusion is changed as a consequence of cardiac output decrease, whereas distributive types of shock are related to a primary dysfunction of the resistive component of the cardiovascular system. In vasoplegia, vascular tone is reduced and there is a noticeably depressed constrictive response of arterioles to vasoconstrictors, and is a main cause is septic shock (Levy et al., 2010). Sepsis-induced vasoplegia is a component of a generalized circulatory dysfunction that involves the macro- and microcirculation, heart, and endothelium, as an outcome of a systemic inflammatory response accumulated by the host in response to invading microorganisms (Hollenberg, 2009). Various evidences accumulated over the past 2 decades has suggested that enhanced formation of free radicals and oxidant species symbolizes a key pathophysiological mechanism of cardiovascular dysfunction and organ damage during sepsis (Pacher et al., 2007). Among such oxidizing agents, the powerful oxidant peroxynitrite has received particular interest as an essential mediator …show more content…
Different types of mechanisms have been put forward to explain peroxynitrite-mediated reduction of vascular tone. Bioenergetic failure associated to the direct effects of peroxynitrite on the mitochondrial electron transport chain, or to DNA-damage-mediated activation of PARP with successive reduction in cellular NAD+ and ATP has been suggested as the primary mechanism connecting peroxynitrite generation with vascular contractile dysfunction (Pacher and Szabó, 2008; Esposito and Cuzzocrea, 2009). Therefore, pharmacological inhibition of PARP (Jagtap et al., 2002; Goldfarb et al., 2002) or its genetic deletion (Soriano et al., 2002; Liaudet et al., 2000) have been linked with significant improvements of vascular contractility and reduced hypotension in different animal models of septic and hemorrhagic shock. Other mechanisms include the opening of KATP channels in response to peroxynitrite, causing induction of vascular hyperpolarization (Li et al., 2004; Ohashi et al., 2005), activation of matrix metalloproteinases (especially MMP-2) in the vessel wall by peroxynitrite (Cena et al., 2010) and ultimately impairment of myosin light chain phosphorylation due to myosin phosphatase activation by peroxynitrite leading to