Selective S-nitrosation of mitochondrial complex I by MitoSNO as a new therapy for cardiac ischaemia-reperfusion injury

Ischaemia-reperfusion (IR) injury underlies many clinically important conditions, such as heart attack and stroke. Ischaemia occurs when the blood supply to an organ is interrupted, for example by a blood clot. If the blood supply is restored the tissue can recover. However, reperfusion of the ischaemic organ with oxygenated blood leads to extensive tissue damage that worsens the long-term prognosis for the patient. This injury is initiated largely by the production of damaging free radicals from mitochondria during reperfusion that leads to cell death. We have developed a novel mitochondria-targeted drug called MitoSNO that prevents free radical production from mitochondria during IR injury. MitoSNO comprises a lipophilic cation that drives its rapid and extensive uptake into mitochondria within the heart immediately following its intravenous injection during reperfusion of the ischaemic organ. Within mitochondria MitoSNO selectively transfers a nitric oxide moiety onto a particular cysteine on respiratory complex I, thereby preventing the mitochondrial free radical production that normally occurs during reperfusion. This modification is reversed after 5-10 mins allowing the mitochondria to return to full activity. Rodent studies have shown that MitoSNO prevents cardiac IR injury in clinically relevant in vivo models, thereby greatly enhancing the long-term recovery of heart function. MitoSNO is unique as no other protective therapies can be applied to organs at reperfusion to block mitochondrial free radical production. In this study MitoSNO will be assessed to see if it is also protective against IR injury in pigs in preparation for a first-in-man Phase I study. As similar IR injury is found in other situations, such as heart attack and organ transplantation, MitoSNO may also prove a useful therapeutic for a range of indications.

Ischaemia-reperfusion (IR) injury underlies the tissue damage during heart attack, often leading to death of the patient or to long term heart damage and health problems in those who survive the initial heart attack. Ischaemia occurs when the blood supply to an organ is interrupted, for example by a blood clot and if the blood supply is restored the tissue can recover. However, reperfusion of the ischaemic organ with oxygenated blood leads to extensive tissue damage that worsens the long-term prognosis for the patient. This injury is initiated largely by the production of damaging free radicals from mitochondria during reperfusion that leads to cell death. We have developed a novel mitochondria-targeted drug called MitoSNO that prevents free radical production from mitochondrial complex I during IR injury. MitoSNO comprises a lipophilic cation that facilitates its rapid and extensive uptake into mitochondria within the heart immediately following its intravenous injection during reperfusion. Within mitochondria MitoSNO selectively transfers its nitric oxide moiety onto a particular cysteine on respiratory complex I, thereby preventing the mitochondrial free radical production that normally occurs during reperfusion. This modification is reversed after 5-10 min allowing the mitochondria to return to full activity. Rodent studies have shown that MitoSNO prevents cardiac IR injury in clinically relevant in vivo models, thereby greatly enhancing the long-term recovery of heart function. MitoSNO is unique as no current protective therapies can be applied to organs at reperfusion to inhibit mitochondrial free radical production. In this proposal MitoSNO will be taken through studies in a pig model in preparation for first-in-man Phase I/II studies. As similar IR injury is found in other situations, such as stroke and organ transplantation, MitoSNO may also prove useful for a range of other indications.

This work sets out to develop a new therapeutic approach to improve the treatment of heart attacks. At the moment, patients experiencing the most deadly form of heart attack, ST-Elevated Myocardial Infarction (STEMI) are treated by removing the blockage to the coronary artery that caused the heart attack as soon as possible. This is done in the "cath lab" by a process called Primary Percutaneous Coronary Intervention (PPCI), also called coronary angioplasty. In this a catheter is inserted via the femoral artery into the blocked coronary artery. Then a balloon is inflated to open up the blood vessel and a stent inserted to maintain blood flow through the artery. The advent of this procedure has been a tremendous advance in decreasing the death rate associated with heart attack, and about 61,000 of these procedures are performed every year in England alone. Despite this, the reperfusion of the ischaemic heart tissue with oxygenated blood during PPCI leads to extensive ischaemia-reperfusion injury to the heart. This damage is major factor contributing to the ~30% mortality suffered by STEMI patients within 30 days of PPCI. Furthermore, those STEMI patients who survive long-term after PPCI often go on to develop chronic heart failure that leads to extensive morbidity and mortality among this group of patients. Therefore the prime beneficiaries of this work will be STEMI patients undergoing PPCI and they will benefit by increased survival and far less long-term morbidity. As chronic medical treatment for ischaemic heart disease in this group of patients is expensive there will also be considerable cost savings for national health systems.