Rescue of the Heart

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However, stimulation of mitochondrial biogenesis, leading to its beneficial effects, is accelerated by targeting other components such as endothelial nitric oxide synthase, adenosine monophosphate-activated kinase, and other mitochondrial biogenesis pathways, which all hold promise in addressing the disease [ 22 , 23 ]. A summary of some common and recent experimental and clinical interventions are presented in Table 1. One of the earlier drugs to be used, an angiotensin-converting enzyme ACE inhibitor named captopril now marketed as Capoten , increased mitochondrial content in canine hearts after coronary ligation [ 24 ].

This indicates that the favorable effects may, in part, be related to mitochondrial invigoration. Current studies have examined the effects of various ACE inhibitors in human patients, including that of captopril. Although captopril is widely used, patients treated with the drug presented higher incidence of coughing, and it was suggested that enalapril is more potent, owing to its effect on ejection fraction, stroke volume, and mean arterial pressure [ 25 ].

A summary of selected common and recent pharmacologic drugs used in mitochondrial targeting of heart failure. Mitochondrial oxidative stress, caused by either ROS overproduction or decreased endogenous antioxidant defenses, has been implicated in the structural and functional alterations during myocardial failure [ 39 ]. Sources of ROS in the failing heart include mitochondrial ETC, nicotinamide adenine dinucleotide phosphate oxidases, nitric oxide synthases, and xanthine oxidase [ 40 ]. The change in oxidative stress levels may contribute to changes in the abundance and copy number of mitochondria, and in the integrity of mtDNA in human cells during pathological conditions [ 41 ].

ROS may act within a threshold to generate stress responses through various cellular processes, such as modifications in specific nuclear genes, in order to maintain energy metabolism and production [ 42 ]. Decreased mitochondrial biogenesis occurs during insignificant increases in oxidative stress, in addition to increased mitochondrial DNA mutations, which eventually lead to impaired OXPHOS and cardiomyopathy. A suggested mechanism involves impairment of cellular and mitochondrial structures, such as excitation-contraction coupling proteins, which affect the mechanical function of the heart [ 44 ].

Considering that majority of the ROS originates in the mitochondria during HF, it is not surprising that these organelles are the most susceptible to oxidative damage. The aforementioned roles of ROS highlight its importance and novelty as a therapeutic target for treating HF. However, it is unclear whether these agents target mitochondrial ROS directly or indirectly [ 47 , 48 ].

Numerous studies have focused on oxidative-stress targets or energetics in HF models. Large randomized trials of antioxidant vitamins such as vitamin E have so far been futile, which might be due to the nonspecific nature of the vitamins, possibly inhibiting both the beneficial and negative effects of ROS. Nevertheless, it has been shown that mitochondrial targeting of ROS-scavenging molecules is protective.

Modulation of substrate utilization with drugs such as perhexiline to increase myocardial energy production has only been performed in small-scale clinical studies [ 49 ]. A two-pronged approach of addressing oxidative stress and mitochondrial dysfunction together has been deemed a more efficient approach. The use of antioxidants such as triphenylphosphonium conjugation MitoQ and novel Mn-SOD, or catalase analogues could be considered in future HF studies. It was earlier thought that the inner-membrane ANT [ 52 ], outer-membrane voltage-dependent anion channel [ 53 ], and inner phosphate carrier [ 54 ] all play essential roles in mPTP induction.

However, recent studies have pointed out that these components only play a supporting, regulatory role, while more compelling evidence points at the importance of matrix protein cyclophilin D CyP-D and mitochondrial ATPase in mPTP structure and regulation [ 55 ]. Determining the structure of mPTP would aid the development of better methods to inhibit mPTP opening, helping in the maintenance of inner-membrane integrity and preservation of ATP production, which would prevent cell death during the onset of HF. Earlier studies involving CsA also revealed cardioprotection from reoxygenation injury in isolated cardiac myocytes [ 56 ].

This was supported by another study where CsA exhibited cardioprotection from reperfusion injury in the Langendorff perfused heart [ 57 ].

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However, owing to its affinity to cytosolic cyclophilin-A, CsA poses a problem regarding cardioprotection, wherein it inhibits calcineurin, which directly affects heart function [ 59 ] and is reported to possess immunosuppressive activity [ 60 ]. In order to address such problems exhibited by CsA, analogues have been developed that are inactive against calcineurin, but still bind strongly to CyP-D.

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The cardioprotective properties of these analogues are similar to that of CsA, and are potent even when administered only during early reperfusion [ 61 - 64 ]. Considering that oxidative stress is a robust mPTP-opening activator, clinical use of ROS scavengers might be effective [ 65 ]. This was associated with cardiac function recovery after ischemia [ 68 ]. Thus, there is a need to develop drugs that are more potent in targeting other aspects of mPTP, without disrupting normal mitochondrial function.

Mitochondria are deemed pivotal in both normal and pathological functioning of the heart, and are implicated as either the primary cause or an aid in the progression of HF.

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There are many other factors that are yet to be considered in order to come up with more successful methods of dealing with HF. Pharmacological intervention may be used in patients at the risk of HF, especially when addressing novel cardiac targets such as mitochondrial PTM [ 71 ]. Briefly, PTMs are conformational changes that occur in a protein after the translational process, in response to external stimuli like ROS or aberrant signaling, and these PTMs significantly affect cellular function [ 7 ].

Taken together, maintaining mitochondrial biogenesis against cardiac injury and decreasing mitochondrial ROS are two promising mechanisms that may lead to effective treatments for HF.

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In addition, results from experiments show that mPTP also holds promise as a target in HF treatment; these experiments should be followed up. No potential conflict of interest relevant to this article was reported. National Center for Biotechnology Information , U. Journal List Int Neurourol J v. Published online Mar Author information Article notes Copyright and License information Disclaimer.

Received Mar 14; Accepted Mar This article has been cited by other articles in PMC. Abstract Heart failure HF is a multifactorial disease brought about by numerous, and oftentimes complex, etiological mechanisms. Open in a separate window. Pharmacological interventions in the mitochondria during heart disease. Mitochondrial Oxidative Stress Mitochondrial oxidative stress, caused by either ROS overproduction or decreased endogenous antioxidant defenses, has been implicated in the structural and functional alterations during myocardial failure [ 39 ].

Conflict of Interest No potential conflict of interest relevant to this article was reported. Epidemiology and risk profile of heart failure. Long-term trends in the incidence of and survival with heart failure. N Engl J Med.

Our adoption process begins with our matchmaking questionnaire. If we find that we have a dog or cat that is well suited to you, we will then schedule a casual meet and greet with our rescued pet and all members of your family that live in your home both 2 and 4 legs.

We have found that by offering training support at the time of adoption, many potential adoption issues are avoided and our adopters learn important tools for success regarless of how many pets you may have had in the past. Immediately following the integration, our adopters typically begin a foster-to-adopt trial with their new pet for about two weeks. This trial period gives adopters and adoptees time to get used to each other, while working with us on any hiccups that may come along.

Key to Lion's Heart Rescue | Adopt. Foster. Donate. Volunteer. Rescue.

Our priority is to make sure that our adopters and adoptees find happiness with each other and we know that that forming this kind of bond can take some time. Think of it as dating before marriage! Moses is a playful, approximately three-year-old Rottie. Moses is a strong, sensitive, playful happy dog who needs a loving leader to create structure and channel Moses' high intelligence into challenges that will keep him from getting bored mentally and physically.

He prefers a high quality low fat diet and a person who is consistent, committed and has used positive reinforcement techniques to train their Rottweilers. If you want balance in your life, and know how to manage your own stress, Moses will be a sweet and loyal companion. He follows direction, and if you put the effort in, you will receive the reward. He requires supervision, attention, love and experience. Moses is neutered, up-to-date on vaccinations, and is microchipped.

He is located in Southern California, but can be brought up to Oregon for the right family. Please go to our website to complete an application quickest way to meet a dog.

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