心力衰竭的小鼠模型| Nature Podcast

来源：Nature自然科研

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音频文本：

Interviewer: Benjamin Thompson

First up on today’s show, I’ve been looking into some new research about heart failure – a very serious condition which is characterised by a weakness of the heart which can’t pump blood effectively around the body. It’s a debilitating, long-term condition which is most common in older people. There are a few different types of heart failure and of the most common is called ‘heart failure with reduced ejection fraction.’

Interviewee: Joseph Hill

That’s the kind of heart failure you get if you have a heart attack, for example, where the heart muscle is injured, part of it is dead and no longer able to contract, and the ability of the heart to expel blood is decreased. That is a disorder that is very common. We see it all the time and we have many, many, many tools to treat that.

Interviewer: Benjamin Thompson

This is cardiologist Joseph Hill from the University of Texas Southwestern Medical Center in the US.

Interviewee: Joseph Hill

Another type is heart failure with preserved ejection fraction (HFpEF). That is a disorder that is just as common as heart failure with reduced ejection fraction, in fact, nowadays, it’s more common.

Interviewer: Benjamin Thompson

Rather than failing to properly expel blood, HFpEF hearts have impaired ability to fill with it. Although these two types of heart failure have similar symptoms – for example, shortness of breath, exhaustion, swollen limbs – when it comes to HFpEF, the treatment options are very different.

Interviewee: Joseph Hill

We have nothing to treat this disorder and it’s a very frustrating clinical situation. What we typically do is we will diurese the patient to eliminate the excess fluid in their lungs and in their belly and in their legs, and that will make them feel better. We will treat their comorbidities, we will treat their hypertension, we will treat their diabetes, but we have nothing at all to treat the root of the problem, what is wrong with the heart itself.

Interviewer: Benjamin Thompson

One of the reasons for the lack of treatment options has been the lack of a suitable model to test them on. While animal models of HFpEF do exist, they don’t necessarily reflect all of the symptoms seen in humans. Joseph is hoping to change that and has this week published a paper in Nature detailing a new mouse model of HFpEF that he thinks mirrors the human syndrome more closely.

Interviewee: Joseph Hill

We took a very simplistic approach – that is, most patients with HFpEF are obese with diabetes and they have high blood pressure, so we decided to make a mouse that’s obese with diabetes and that has high blood pressure.

Interviewer: Benjamin Thompson

By feeding the mice a high-fat diet and administering a drug to raise their blood pressure, the team were able to mimic many of the characteristics of HFpEF in humans, including impaired filling of the heart, exercise intolerance and lung congestion. Having this model allowed Joseph and his colleagues to look for a mechanism underlying HFpEF in these mice. It turns out that an enzyme called iNOS was being overproduced in the mouse hearts. This enzyme makes the molecule nitric oxide, or NO, which is important for many physiological processes, so having increased levels of the iNOS enzyme was having effects on other proteins in the mouse hearts.

Interviewee: Joseph Hill

The animal is flooded with NO and what that NO does is it covalently couples to many, many, many different proteins, including one of them that plays a significant role in the unfolded protein response. 

Interviewer: Benjamin Thompson

The unfolded protein response is a set of emergency measures that stressed cells activate when faced with a build-up of incorrectly folded proteins – something that is very bad for cells. In a number of heart disorders, the unfolded protein response is switched on in response to cellular stress, but in the HFpEF mice, it was switched off as a result of the excess nitric oxide. This was a surprise for Joseph, and could represent a new mechanism underlying HFpEF. The unfolded protein response was also found to be downregulated in heart biopsies from humans with HFpEF, showing some similarity between the animal model and the human syndrome. Joseph says though that this work is only looking at one potential mechanism, and there could be a lot more going on.

Interviewee: Joseph Hill

There are many proteins that are covalently altered by this surfeit of NO and we haven’t begun to look at all of them – there are many of them. So, what we have found is that this excess NO is crippling the unfolded protein response, but it’s entirely possible that there are many other events going on as well, that the NO coupling to other proteins is doing important things that we haven’t begun to figure out yet.

Interviewer: Benjamin Thompson

Regardless, just having an animal model of HFpEF that shows many of the symptoms seen in humans will likely be of benefit to other researchers, according to Elizabeth Murphy from the National Heart, Lung and Blood Institute in the US, who wasn’t involved in the study.

Interviewee: Elizabeth Murphy

The main utility of this to me as a cardiac researcher is it now gives a new tool to study drugs. HFpEF is 50% and growing of the patients with heart failure, and if I want to say does this drug work for HFpEF patients, I have no model to test it in. So, now I at least have a model and I think many researchers in the field will be testing their drugs on this model.

Interviewer: Benjamin Thompson

Elizabeth thinks that because HFpEF is caused by such a complex range of factors, care must be taken to tweak the new mouse model – perhaps by using different methods to induce the condition – to see if the downstream manifestations of HFpEF is the same each time. In humans, HFpEF affects more women than men, perhaps by as much as two to one. Elizabeth also says that this is something that needs to be considered when developing future models for HFpEF.

Interviewee: Elizabeth Murphy

The study seems to be primarily carried out in male animals, and I think it would be important to see whether if they did these studies in female animals, would they get a similar result? And furthermore, they show a role for iNOS in the unfolded protein response. Since there are metabolic differences particularly in the way iNOS is regulated in males and females, would they get a similar upregulation of iNOS in female mice?

Interviewer: Benjamin Thompson

Joseph told me he is currently researching how sex differences in mice might affect HFpEF. He also says that the current animal model is just a start and won’t necessarily be representative of everyone with the condition. 

Interviewee: Joseph Hill

HFpEF is notoriously heterogeneous and I don’t mean to suggest that this model is HFpEF for everybody. I believe, based on my reading of the literature, that this is sort of garden-variety HFpEF – it is certainly a very common manifestation – but I don’t mean to suggest that this is all of HFpEF because it’s probably not.

Interviewer: Benjamin Thompson

Whether this new model represents all of HFpEF or not, it gives researchers a new place to start when looking at the mechanisms underlying this complex and currently untreatable condition that affects millions of people worldwide. You can read Joseph’s paper, and a News and Views article about the work over at nature.com.ⓝ

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