Researchers from Johns Hopkins and elsewhere report
what is believed to be the first direct
evidence in lab animals that the erectile dysfunction drug
sildenafil amplifies the effects of a heart-protective
The team's findings, published in the Journal of
Clinical Investigation online Jan. 5, help explain
why sildenafil, more widely known as Viagra, has already
been shown to improve heart function and may
one day have value in either treating or preventing heart
damage due to chronic high blood pressure.
The key, investigators say, is sildenafil's effects on
a single protein, RGS2, newly identified in
the latest study as an essential link in the chain
reactions that initially protect the body's main
blood-pumping organ from spiraling into heart failure.
Experimenting in mice, the team of heart experts first
established that after a week of
induced high blood pressure, the hearts of animals
engineered to lack RGS2 (regulator of G-protein
signaling 2) quickly expanded in weight by 90 percent, and
almost half the mice died of heart failure.
In mice with RGS2, by contrast, the dangerous muscle
expansion, known as hypertrophy, was delayed,
growing only 30 percent, and no mice died.
Subsequent tests treating hypertensive mice that had
RGS2 with sildenafil showed enhanced
buffering, with less hypertrophy, stronger heart muscle
contraction and relaxation, and as much as 10
times lower stress-related enzyme activity compared to
their untreated counterparts. In mice lacking
RGS2, sildenafil had no effect.
"Sildenafil clearly prolongs the protective effects of
RGS2 in mouse hearts," said study senior
investigator and cardiologist David Kass, a professor at
the Johns Hopkins University School of
Medicine and its
Heart and Vascular Institute.
According to Kass, RGS2 is stimulated by an enzyme,
protein kinase G, whose action is, in turn,
raised by countering the activity of another enzyme,
phosphodiesterase 5, or PDE5A. Sildenafil's
ability to block PDE5A was shown by Kass and his team in
2005 to be responsible for blunting
hypertrophy due to high blood pressure in mice and
offsetting similar, adrenaline-stimulated heart
stress in people.
Kass said that RGS2 "acts like a short-term reset
mechanism in the heart," recoupling G
proteins that if left alone stimulate the heart's response
to high blood pressure. And without the
"reset," a cascade of reactions known as Gq signaling leads
to scar tissue formation, hypertrophy and
Currently, physicians use so-called ACE inhibitor and
ARB inhibitor drugs to block Gq signaling.
These classes of drugs are the most common treatment for
heart failure, which afflicts more than 5
million Americans, killing over a quarter million of them
"The evidence is piling up that unbridled Gq signaling
is driving a central biological chain reaction
in heart failure," Kass said, "and that by extending the
protective effects of RGS2 or by developing a
test for its presence, researchers can develop new
therapies or improve existing ones, including ACE
inhibitors and possibly sildenafil, for people with heart
failure who will benefit most."
Until recently, scientists thought RGS proteins, which
are found only in small quantities in the
heart — a thousand times less than other, more common
proteins, such as myosin and metabolic
proteins — played no key role in heart function.
Previous tests in mice, Kass says, had shown no harmful
effects to the heart from knocking out production of RGS2,
though the protein was known to have a
role in maintaining smooth muscle function in blood
But studies by co-investigators at Tufts Medical
Center in Boston had shown that RGS2 activity
was upped by protein kinase G, leading Kass and others to
look for stronger links between these
biological pathways and hypertrophy.
The latest study involved more than a half-dozen
experiments, all performed within the last
three years and designed to zero in on the role played by
RGS2 in stalling hypertrophy.
In one experiment for the current study, researchers
artificially stimulated the Gq chemical
pathway in mice lacking RGS2, worsening the effects of Gq
signaling, including hypertrophy and
widened heart chambers.
In another experiment in mice with and without RGS2,
researchers analyzed the cardiac
response to the physical stress of twice-daily swimming
exercises lasting 90 minutes each, a stress
not known to affect Gq signaling. After six weeks of
testing, both sets of mice showed similar
increases, at 30 percent, in heart mass and no signs of
impaired heart function.
Subsequent protein analysis for enzymatic action
common to heart failure showed the same
results for both sets of mice, confirming to researchers
that RGS2 proteins were responsible for
protecting the heart from hypertrophy linked to Gq
More tests with pressure overload showed that when
RGS2 was stimulated by protein kinase G,
the two proteins moved together from inside the cell to its
outer cell walls. This effect was then
stabilized in RGS2 mice treated with sildenafil,
solidifying evidence of the biological chain reactions
between the drug and the protein.
"Our results offer among the first insights into the
biology of the RGS2 protein in heart cells
during hypertrophy," said study lead investigator Eiki
Takimoto. "This greatly expands our
understanding of how high blood pressure affects the heart
and helps break down the disease
equation into its molecular components for subsequent
Takimoto, an assistant professor at Johns Hopkins,
said that the team's next plans are to look
at other potential consequences of increased RGS2 activity
within the cell and to zero in on what
other proteins or factors boost its action.
PDE5A is involved in the breakdown of a key molecule,
cyclic guanosine monophosphate, which
helps to control stresses and limit overgrowth in the
heart. PDE5A is also the biological pathway
blocked in the penis by sildenafil to promote the
relaxation of blood vessels and maintain erections.
Funding for the reported study was provided by the
National Institutes of Health, the Peter
Belfer Laboratory Foundation and the American Heart
In addition to Kass and Takimoto, Johns Hopkins
researchers involved in this study were
Norimichi Koitabashi, Steven Hsu, Elizabeth Ketner, Manling
Zhang, Takahiro Nagayama, Djahida
Bedja and Kathy Gabrielson. Kass is also the Abraham and
Virginia Weiss Professor of Cardiology at
Additional assistance was provided by Michael
Mendelsohn and Robert Blanton, at Tufts Medical
Center, and David Siderovski, at the University of North
Carolina at Chapel Hill.