Wednesday, September 26, 2012

Side effect of Angiotensin II


Angiotensin II (ANGII) is a hormone that can cause problematic changes in the heart such as inflammation, thickening of the walls of the heart, high blood pressure and fibrosis (excessive scar tissue).  One pathological change the lab I work for studies is cardiac fibrosis (excessive scar tissue) caused by angiotensin II. The heart consists mostly of two types of cells: myocytes and fibroblasts. Fibroblasts are cells in connective tissue that are involved in tissue repair.  They are located between myocytes and contribute to the structure and mechanical properties of the heart.  Fibroblasts have a receptor called angiotensin type I receptor (AT1R).   When Angiotensin II binds to the angiotensin type I receptor, a signaling pathway is activated in the cardiac fibroblasts.  This leads to an increase production of cytokines in the fibroblast.  Cytokines are signal proteins. One cytokine that is made is the transforming growth factor beta (TGFβ).  TGFβ is secreted from the cardiac fibroblast to recruit other fibroblasts to this area in the heart.  The fibroblasts also secrete extracellular matrix (complex network of proteins), that are rich in collagen.  This creates a scar.  Many types of immune cells are recruited to this area too.  This cascade of events leads to fibrosis (excessive scar tissue).  Below are two pictures of a section of a mouse heart that has angiotensin II induced fibrosis from my lab. 

 The red in this section of mouse heart is the fibrotic regions made up of the extracellular matrix.  The heart section is stained with Picro Sirius Red that binds to collagen and turns it red.

 The arrows point to white blood cells (red nuclei) in the fibrotic area of a mouse heart.  

I work for a lab that looks at the effects certain drugs have on the angiotensin II signal pathway in the heart.  We implant pumps into mice that release angiotensin II and expose them to different drugs by injections.  Then we look at cardiac fibrosis by staining sections of the mice’s hearts (as seen in the pictures above).  We also look at the quantity and type of immune cells in the heart and venous blood from the mice.  I have many questions from the experiments my lab has done such as: What is the mechanism that triggers the immune response in the fibrotic areas of the heart?  Where do the immune cells come from (lymph nodes, bone marrow)?  Where do the fibroblasts come from that are recruited by the cytokine TGFβ (bone marrow, other surrounding tissues next to the heart)?

Sources:
Leask A. TGFβ, cardiac fibroblasts and the fibrotic response.  Cardiovascular Research 2007;74:207-212.

Mehta P, Criendling K.  Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system.  Am J Physiol Cell Physiol 2007;292:C82-C97.

Mckinsey lab in the division of cardiology.  

1 comment:

  1. It was very interesting to see the effects of Angiotensin II in the vasculature as well as in the heart. Hopefully, this will help reinforce the importance of blood pressure management, not just by physicians (who already know this) but also by patients and educators, Fortunately, we have been able to manipulate the renin-angiotensin-aldosterone system and use it to our advantage (http://upload.wikimedia.org/wikipedia/commons/a/a2/Renin-angiotensin-aldosterone_system.png). Angiotensinogen is converted to Angiotensin I, which is converted to Angiotensin II by ACE (angiotensin-converting enzyme) in the lung. When angiotensin II binds to the receptors, it causes the effects, including secretion of aldosterone from the adrenal cortex.

    What pharmacologists have done is take advantage of the RAAS. We have ACE inhibitors (lisinopril, captopril), calcium-channel blockers (verapamil, amilodipine, and nefidipine) angiotensin-receptors blockers (losartan) and even aldosterone blockers (spironolactone).

    However, the first-line effort is lifestyle modifications. Essentially, reduce the intake of salt, alcohol, and fatty foods, and engage in stress-relieving activities such as cardiovascular exercise (jogging) meditation, yoga, or tai chi.

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